Energy metabolism and chronic diseases -
Regardless of diabetes type, odds of hospitalization and worsening disease severity were more than 3-fold higher than in individuals without diabetes 8. A recent study estimated the global prevalence of diabetes according to COVID severity The prevalence of diabetes rose with increasing disease severity, from Among the latter, diabetes prevalence increased from Nonalcoholic fatty liver disease NAFLD , defined by increased hepatic lipid accumulation in the absence of any other specific cause 32 , 33 , has been also associated with increased COVID severity, the risk of severe disease ranging from to 2.
The risk of severe COVID outcomes increases in near-linear manner with the number of components of the metabolic syndrome impaired fasting glucose or diabetes, elevated blood pressure, hypertriglyceridemia, low high-density lipoprotein-cholesterol, or abdominal obesity , even after correction for BMI Obesity and diabetes also appear to increase the risk of PASC.
A prospective observational cohort study of COVID symptoms in more than adults found that the likelihood of persistent symptoms increased with increasing BMI The risk of persistent symptoms is also elevated in individuals with preexisting diabetes 18 , COVID survivors, even those who did not require hospitalization, are at higher risk of death and are more likely to use health care resources compared with people without COVID because of a wide range of incident physical and psychological symptoms The burden of post-acute sequelae is greater in individuals previously hospitalized for COVID compared to those with seasonal influenza, suggesting disease-specific persistence of clinical manifestations An excess burden of obesity, diabetes and hyperlipidemia has also been observed in people with a history of COVID Similar to SARS-CoV 43 , 44 , COVID can result in new-onset hyperglycemia or worsening glycemic control 45 , 46 , and new-onset type 2 diabetes is often listed among the long-term adverse consequences of COVID Other data support that the risk of developing diabetes is highest during the acute phase and only in those who were hospitalized for COVID, whereas it attenuates over time SARS-CoV-2 infection appears to promote the progression to diabetes in people with a history of prediabetes, but again only in individuals previously hospitalized for COVID Predictors of persistent diabetes at 5 months in those people comprise in-hospital diabetes diagnosis hazard ratio [HR], The latter, however, was a strong predictor of in-hospital diabetes HR, 1.
Several studies have compared the risk of persistent diabetes following the acute phase in adults with COVID vs adults with other respiratory illness 42 , Table 1.
These estimates are based on a diagnosis of type 2 diabetes within days after diagnosis of COVID or influenza and might therefore include persons with previously undiagnosed diabetes. A more recent study found that the incidence of new-onset type 2 diabetes during hospitalization was 3.
Of those with no evidence of diabetes during hospitalization, A diagnosis of type 2 diabetes during hospitalization, age, congestive heart failure, steroid therapy, intensive care unit admission, and D-dimer were significant predictors of diabetes at follow-up.
Longer term studies confirm that glycemic control improves over time. Among people diagnosed with diabetes during hospitalization for COVID, Also, reinfection with SARS-CoV-2 is associated with higher diabetes risk HR, 1. Anti-SARS-CoV-2 vaccination mitigates the risk of PASC but does not confer full protection in individuals with breakthrough infection, with the HR for metabolic disorders including diabetes and hyperlipidemia being 1.
Studies that compared the risk of diabetes in adults with COVID vs adults with other respiratory illness. Abbreviations: AURI, acute upper respiratory tract infections; DM, diabetes mellitus; HR, hazard ratio; IR, incidence rate per person-years; IQR, interquartile range; IRR, incidence rate ratio; OR, odds ratio; RR, relative risk; SHR, subdistribution hazard ratios; VLRTI, viral lower respiratory tract illness.
Follow-up data are a days, median IQR or b days, mean. Despite the possibility that some people had previously undiagnosed diabetes before developing COVID and that individuals who had COVID undergo more intensive screening for medical conditions compared with uninfected people 61 , there is now a large body of evidence that COVID is associated with an increased diabetes risk, which is highest during the acute phase of COVID 19 , Considering the large number of individuals affected by COVID worldwide, these rates appear worrisome and suggest that the COVID pandemic will cause a dramatic surge in the future number of people with diabetes globally.
SARS-CoV-2 enters cells via binding of the transmembrane spike glycoprotein to the angiotensin-converting enzyme-related carboxypeptidase ACE2 receptor 62 , a type I integral membrane peptidase that cleaves angiotensin II into angiotensin , a peptide with protective effects on several organs and systems The virus is then either 1 internalized via clathrin-mediated endocytosis and the spike protein is cleaved by cathepsins, which prompts fusion of the viral and endosome membranes to release viral RNA into the cytosol, or 2 undergoes cleavage of the spike protein by the transmembrane protease serine 2 TMPRSS2 on the cell surface, which allows membrane fusion and penetration of viral RNA into the cytosol Other host factors such as neuropilin 1 NRP1 and furin are involved in SARS-CoV-2 entry or spike protein activation SARS-CoV-2 infection is asymptomatic or causes mild, flu-like symptoms in most cases.
The following paragraphs will address the mechanisms by which preexisting metabolic alterations may increase COVID severity. Obesity is a chronic relapsing progressive disease 67 characterized by abnormal fat mass and distribution and associated with several diseases including cardiovascular disease, diabetes, dyslipidemia and NAFLD Over time, the excessive fat accumulation leads to abnormal expansion of white adipose tissue with adipocyte hypertrophy enlarged cells and hyperplasia increased number of new smaller cells 69 , 70 , which varies individually and depends on the respective adipose tissue compartment.
Adipose tissue expansion is paralleled by local angiogenesis to supply nutrients and oxygen to adipocytes. The sequence of events seems to be hypertrophy followed by angiogenesis and hyperplasia favoring local hypoxia and adipose tissue dysfunction Specifically, visceral adipose tissue exhibits lower angiogenic capacity with higher risk of hypoxia Adipocyte hypoxia triggers local inflammation with release of chemotactic signals and proinflammatory cytokines and subsequent recruitment of macrophages with altered polarization, ultimately leading to fibrosis and adipocyte death Activation of this pathway impairs insulin signaling and causes insulin resistance with impaired insulin-induced suppression of white adipose tissue lipolysis.
This causes lipid overflow to other organs, triggering a cascade of events that eventually results in increased gluconeogenesis and fasting glucose production, and ectopic fat accumulation leading to lipotoxicity and multiorgan insulin resistance Mechanical stress on the adipocyte, release of damage-associated molecular proteins from dying adipocytes, activation of inflammatory signaling by free fatty acids FFA through the Toll-like receptor 4 or Toll-like receptor 2 on the adipocyte's plasma membrane, endoplasmic reticulum ER , and oxidative stress also contribute to adipose tissue inflammation and insulin resistance These early mechanisms contribute to the onset of a local inflammation that over time leads to spillover of pro-inflammatory cytokines and adipokines into the systemic circulation, worsening the multiorgan insulin resistance triggered by excess release of lipids from adipose tissue Adipose tissue macrophages are the main source of adipose tissue-derived pro-inflammatory cytokines and play a key role in the development of systemic inflammation, insulin resistance, and type 2 diabetes 79 , Eventually, the changes induced by excess adiposity cause local and systemic maladaptive, chronic low-grade inflammation, contributing to systemic insulin resistance To overcome insulin resistance, β cells secrete a greater amount of insulin leading to hyperinsulinemia, which stimulates further expansion and dysfunction of adipose tissue.
Over time, if excess adiposity is maintained, these alterations persist and β-cell function declines, causing fasting and postprandial hyperglycemia, and overt diabetes Longstanding adipose tissue dysfunction leads to altered expression and secretion of adipose-tissue specific cytokines adipokines involved in the regulation of energy metabolism, appetite regulation, and proinflammatory and immune responses.
A lower expression of anti-inflammatory adipokines eg, adiponectin and higher expression of proinflammatory adipokines eg, leptin, resistin, visfatin contributes to the systemic subclinical inflammation and progressive insulin resistance with increased risk of type 2 diabetes Alterations in the secretion of adipokines also play a role in obesity-related immune dysfunction.
Immune cells are especially sensitive to changes in the lymphocyte microenvironment because they depend on extracellular nutrient uptake for survival and functioning The ILlike adipokine leptin, whose levels increase proportionally to fat mass 95 , is involved in both innate and adaptive immune responses Leptin increases the number of T H 1 and T H 17 cells in both mice and humans and is necessary for glucose uptake via the glucose transporter GLUT1 of activated effector T cells, thereby allowing energy-dependent processes such as T-cell proliferation and cytokine production Hyperleptinemia in obesity is therefore thought to contribute to altered immunity by affecting immune cell metabolism The role of adiponectin in immunity has been explored less than that of leptin.
Adiponectin exerts insulin sensitizing and anti-inflammatory effects and is reduced in obesity Finally, although the abundance of mitochondria in adipocytes is lower compared with other cell types, these organelles play an important role in energy homeostasis in adipose tissue, being key to metabolic processes such as adipogenesis, lipogenesis, fatty acid esterification, and lipolysis Obesity is associated with abnormal mitochondrial function in adipose tissue, with reduced mitochondrial biogenesis, downregulation of genes encoding for components of the mitochondrial respiratory complex, and decreased oxidative phosphorylation These alterations may contribute to, and further aggravate, adipose tissue inflammation and insulin resistance in obesity Several studies have demonstrated that SARS-CoV-2 can infect adipocytes, and that obesity and diabetes enhance the expression of SARS-CoV-2 entry factors in adipose tissue Adipocytes express the SARS-CoV-2 entry factors ACE2, TMPRS2, transferrin receptor, NRP1, and Furin ACE2 is highly expressed in adipose tissue, and its expression is amplified in obesity and obesity-related NAFLD , ACE2 expression is greater in visceral adipocytes, which are more susceptible to SARS-CoV-2 infection than subcutaneous adipocytes Additionally, following SARS-CoV-2 infection, visceral adipocytes show significantly higher expression of proinflammatory genes such as TNFA and IL6 compared with subcutaneous adipocytes A Mendelian randomization analysis confirmed that adiposity, particularly central adiposity defined by increased waist-to-hip ratio , associates with risk of COVID susceptibility, hospitalization, and disease severity, which is mediated at least partly by plasma ACE2 The glucose-regulated protein 78 GRP78 is an ER-associated protein that is translocated to the cell surface under stress conditions, and is highly expressed in adipose tissue, particularly visceral adipose tissue GRP78 facilitates the binding of the spike protein to the ACE2 receptor , and is upregulated by aging, obesity, diabetes, and hyperinsulinemia Thus, excess visceral adipose tissue in obesity could serve as a reservoir for SARS-CoV A role in the onset of systemic, uncontrolled inflammation in COVID can be hypothesized for several mechanisms involved in insulin resistance and inflammation in adipose tissue.
Obesity-related chronic, low-grade systemic inflammation affects immune function and the lung's response to acute infection Elevated levels of pro-inflammatory cytokines, both systemically and in the lungs, favor the development of more severe lung damage in response to infection , Type I interferons IFNs, mainly IFN-α and IFN-β , play a key role in the innate immune response to viral infections, including SARS-CoV-2 infection The stimulator of interferon genes STING pathway mediates type I interferon IFN inflammatory responses in immune cells and is involved in the immune response for various respiratory inflammatory conditions.
STING is considered to be a molecular connection between immunity and metabolism Activation of STING in obesity increases the pro-inflammatory capacity of lung macrophages, a potential mechanism underlying obesity-related lung inflammation Notably, STING is a major contributor to the aberrant type I IFN response in COVID, which amplifies the inflammatory response during the late phase of SARS-CoV-2 infection Of note, infection of mice with murine beta coronavirus A59 increases NLRP3 inflammasome-mediated inflammation Endothelial damage is another prominent feature of COVID Binding of SARS-CoV-2 to the ACE2 receptor reduces ACE2 and the conversion of angiotensin II to angiotensin , thereby increasing the levels of angiotensin II , which has detrimental effects on glucose metabolism On SARS-CoV-2 infection, elevation of angiotensin II levels and the increased release of the proinflammatory cytokines IL-1 and IL-6 induce endothelial activation and increase vascular permeability and expression of adhesion molecules, contributing to the development of a prothrombotic phenotype Circulating levels of plasminogen activator-1, which inhibits plasma fibrinolytic activity and is secreted by several cell types including visceral fat adipocytes and macrophages , are elevated in obesity and associate with detrimental metabolic and prothrombotic effects , Plasminogen activator-1 is elevated in individuals with severe COVID , , possibly contributing to the increased risk of venous thrombosis seen in people with obesity and COVID In addition, obesity-induced endothelial dysfunction because of adipose tissue-derived endocrine and paracrine signals such as adipokines and extracellular vesicles carrying bioactive molecules causes endothelial dysfunction , thereby further worsening SARS-CoVinduced endothelial damage.
White adipose tissue adipocytes are a major source of the tryptophan-derived metabolites, collectively known as kynurenines Most tryptophan is catabolized via the kynurenine pathway, which yields biologically active kynurenines such as quinolinic acid, kynurenic acid, and kynurenine, and the nicotinamide adenine dinucleotide, a cofactor in mitochondrial energy production and several enzymatic redox reactions , This is mainly because of reduced conversion of kynurenine to kynurenic acid, and contributes to impaired lipid homeostasis and insulin sensitivity in adipocytes Infections and inflammation are other conditions in which there is an enhancement of the kynurenine pathway.
In fact, proinflammatory cytokines shift the metabolism of tryptophan toward the kynurenine pathway aiming to provide energy nicotinamide adenine dinucleotide to activated immune cells Nevertheless, kynurenines also have an immunosuppressive effect, which is needed to resolve the inflammatory response A preexisting elevation of kynurenine in individuals with obesity or type 2 diabetes likely contributes to the increased kynurenine levels and kynurenine to tryptophane ratio that has been reported in severe COVID Of note, activation of the kynurenine pathway in individuals with COVID correlates with high IL-6 levels and, by blunting the immune response, may facilitate SARS-CoV-2 infection and the development of severe disease , People with diabetes generally develop more severe COVID than those without diabetes, showing a higher incidence of lymphopenia and increased biomarkers of inflammation Type 2 diabetes is a proinflammatory condition , characterized by higher levels of IL-6, IL-8, and TNF-α, which are associated with worse clinical outcomes and are highest in the presence of comorbidities Individuals with COVID and type 2 diabetes were reported to have significantly greater levels of T H 1 cytokines such as IFN-γ, and IL-6 compared with individuals with COVID, but not diabetes , The presence of diabetes or hyperglycemia due to other causes can affect COVID clinical outcomes in multiple ways.
Having diabetes may increase the susceptibility to SARS-CoV-2 infection. Studies in rodent models indicate that the expression of ACE2 is increased in diabetes , , and particularly type 2 diabetes was shown to be associated with increased ACE2 expression , Hyperglycemia induces glycation of several proteins, including ACE2, which either facilitates or reduces binding of SARS-CoV-2 to ACE2, depending on the site of glycation , Furthermore, increased levels of TMPRSS2 and furin have been reported in hyperglycemia and diabetes.
Individuals with diabetes have impaired innate immunity, including blunted neutrophil and macrophage chemotaxis and function, as well as impaired adaptive immunity and altered cytokine secretion. These derangements in host cellular responses may contribute to their increased risk to develop severe COVID Consistently, poorer glycemic control in people with type 2 diabetes has been linked to greater mortality compared with better glycemic control , likely via hyperglycemia-mediated inhibition of lymphocyte proliferation In-hospital hyperglycemia, regardless of the presence of diabetes, is common and is associated with poor clinical outcomes not only in COVID, but also in a range of different clinical conditions The impact on clinical outcomes is generally greater in individuals with new-onset hyperglycemia compared with those with preexisting diabetes , , and COVID is no exception , An impairment in the innate immune responses caused by acute hyperglycemia may also contribute Hyperglycemia was also shown to enhance SARS-CoV-2 replication and the production of proinflammatory cytokines such as TNF-α and IL-6 in monocytes in vitro Thus, preexisting diabetes may increase vulnerability to SARS-CoV-2 infection 7 , and the risk of unfavorable clinical outcomes 8.
This suggests that diabetes per se renders individuals more prone to severe COVID compared with normoglycemic individuals without diabetes. Acute hyperglycemia, particularly in those without pre-existing diabetes, may act through different pathways, contributing to worse outcomes.
This section examines the effects of SARS-CoV-2 infection on the main organs orchestrating glucose metabolism to better elucidate the relationship between COVID and disrupted glucose metabolism.
The inflammatory and antiviral response to SARS-CoV-2 infection is more prominent in visceral than subcutaneous fat Fig. Preclinical studies have shown that SARS-CoV-2 infection induces adipocyte dysfunction Fig.
Reduced adiponectin is a hallmark of obesity, particularly central obesity Low circulating adiponectin levels have been reported in people with COVID compared with healthy controls , , , the reduction generally being greater with increasing disease severity , Similarly, leptin levels are increased , , unaffected , , , or even reduced Of note, lower adiponectin-to-leptin ratio, a surrogate of adipocyte function , showed an association with worse COVID outcomes , , , , COVID and the adipose tissue see also Table 2.
Main preclinical studies assessing the effect of SARS-CoV-2 infection on adipose tissue. a Granulocyte activation, phagocytosis, adaptive immune response. In addition to the adiponectin-to-leptin ratio, other mechanisms may contribute to systemic insulin resistance in individuals with severe COVID SARS-CoV-2 infection upregulates the RE1-silencing transcription factor REST , which modulates the expression of myeloperoxidase MPO , apelin, and myostatin Specifically, REST upregulates MPO, which was shown to increase the expression of genes involved in gluconeogenesis in hepatocyte cell lines G6pc and adipocytes Pck1 and to induce insulin resistance in adipocytes, preadipocytes, and myotubes.
REST also downregulates the expression of apelin and myostatin, which have opposite effects to MPO In murine adipose tissue, SARS-CoV-2 upregulates the interferon regulatory factor 1 IRF1 , which acts as both a transcriptional activator and repressor to regulate interferon and cytokine responses In addition, the elevation of circulating FFA in people with COVID , , reflects excessive lipolysis, which is likely due to adipose tissue insulin resistance, but can also result from stress-induced hormones such as cortisol or adrenalin, similar to sepsis High levels of circulating long-chain polyunsaturated fatty acids and low levels of long-chain acylcarnitines have been also reported in individuals with COVID, suggesting an increased activity of phospholipase A2 PLA2 , which is required for replication of other coronaviruses Increased PLA2 activity leads to greater production of omega-6 polyunsaturated fatty acid-derived bioactive metabolites such as eicosanoids and oxylipins, which may enhance both SARS-CoV-2 propagation and the inflammatory response Increased expression of PLA2 and zinc-alpha2 glycoprotein a potent promoter of β-adrenergic-driven lipolysis in adipose tissue and reduced levels of circulating adiponectin have previously been reported during intensive care for subarachnoid hemorrhage An increase in zinc-alpha2 glycoprotein is also a risk factor for severe COVID odds ratio, 1.
Notably, administration of lipolysis inhibitors reduced viral replication in mature adipocytes and significantly reduced mortality, alleviated lung pathology, and blunted virus replication in SARS-CoVinfected hamsters Finally, COVID may have a detrimental impact on body composition.
Clinically relevant weight loss during COVID is common even in mild forms and is followed by weight regain with increased abdominal adiposity In a study that compared changes in body composition and insulin resistance as assessed by homeostasis model assessment of insulin resistance [HOMA-IR] in people with or without COVID, the former showed an increase in percentage fat mass despite a reduction in BMI, and significant increases in fasting plasma glucose, insulin, and HOMA-IR compared to pre-COVID These data suggest an association of COVID and possibly other factors, such as inactivity, reduced food intake during illness, and increased food intake during recovery, with worsening body composition and glucose metabolism.
In summary, adipose tissue, particularly visceral adipose tissue, is a main target of SARS-CoV-2, which may induce adipose tissue insulin resistance and adipocyte dysfunction, with altered secretion of cytokines and adipokines contributing to systemic insulin resistance.
The expression of known SARS-CoV-2 entry receptors and facilitators, including ACE2, TMPRSS2, procathepsin L, Ras-related protein Rab-7a, and GPR78 has been reported in liver autopsy samples from individuals who died from COVID , Because the ACE2 receptor is mainly expressed by cholangiocytes , and Kupffer cells , the ability of SARS-CoV-2 to enter hepatocytes and exert cytopathic effects has been debated, also because of a paucity of histopathological studies having investigated the presence of the virus in liver samples Some reported absence of viral RNA, proteins, or viral inclusions in hepatocytes , whereas others were able to detect viral inclusions or the SARS-CoV-2 spike protein , , , , viral entry possibly being facilitated by the high-density lipoprotein scavenger receptor class B member 1 , , a plasma membrane receptor for high-density lipoprotein cholesterol that also facilitates cell entry by the hepatitis C virus These figures are greater than the prevalence of NAFLD in the general population A possible explanation is an over-representation of individuals with liver steatosis in autopsy series, owing to the association between NAFLD and severe COVID Nevertheless, this association disappears when demographic and comorbid factors are taken into account, with BMI and adiposity retaining a causal relationship with severe COVID Distinguishing between preexisting steatosis and SARS-CoVinduced steatosis is challenging.
Potential mechanisms by which COVID might cause or worsen hepatic steatosis and other metabolic derangements are discussed in the following paragraphs and illustrated in Fig. Hepatocellular ER stress is known to be involved in the pathophysiology of NAFLD , In vitro, SARS-CoV-2 infection was shown to rapidly induce ER stress in human cell lines , and dilation of the ER in hepatocytes has been detected by transmission electron microscopy , , Furthermore, the ER-resident chaperone GRP78, a stress marker involved in the unfolded protein response a pathway preventing accumulation of unfolded and misfolded proteins by promoting autophagy and ER-associated degradation that in ER stress conditions is translocated to the cell surface, where it can serve as a multifunctional receptor, including for virus entry , mediates—at least in part—SARS-CoV-2 entry into hepatocytes COVID and the liver.
A Mechanisms by which COVID might cause or worsen hepatic steatosis. B Mechanisms by which COVID might increase hepatic endogenous glucose production. Transmission electron microscopy of postmortem liver biopsies showed marked swelling of mitochondria in hepatocytes of individuals with COVID , Similarly to what has been observed in primary cells, cell lines, and biological samples from people with COVID , SARS-CoV-2 infection in the liver induces downregulation of several genes responsible for oxidation reduction, oxidative phosphorylation, and cellular respiration , , indicating altered mitochondrial function.
Hepatic mitochondria play a fundamental role in energy production via oxidation of amino acids, pyruvate, and fatty acids. An impairment of this adaptation renders mitochondria unable to handle the excess flux of substrates to the liver and is involved in the development of NAFLD and its progression to nonalcoholic steatohepatitis and liver fibrosis In fact, although people with obesity and NAFLD exhibit increased mitochondrial oxidative capacity compared with lean counterparts, individuals with nonalcoholic steatohepatitis and those with type 2 diabetes or histological evidence of liver fibrosis lose the ability to adapt their oxidative capacity to increased lipid loading.
Fatty acid β-oxidation was found to be both upregulated , and downregulated in autoptic liver samples from individuals with COVID, which may reflect different stages of fatty liver disease , Furthermore, higher levels of circulating FFA were found in individuals with critical COVID compared with those with mild disease or no SARS-CoV-2 infection , , being associated with lipotoxicity and worse inflammation, intravascular thrombosis, organ failure, and mortality Upregulation of fatty acid biosynthesis has also been detected in the liver of individuals with COVID Overall, the evidence supports ER stress and abnormal hepatic mitochondrial function in COVID These mechanisms are established contributors to NAFLD , , and favor hepatic lipid accumulation and excess oxidative stress.
This mechanism has served to explain the development or worsening of fatty liver disease in people with COVID The results of a study that examined individuals who had been hospitalized for severe COVID and were reassessed approximately 5 months from symptom onset are consistent with a steatosis-promoting effect of COVID NAFLD was present in The liver plays a major role in glucose homeostasis as the main site for gluconeogenesis 82 , Excessive lipid availability induces insulin resistance in the liver, which manifests as the inability of insulin to suppress hepatic gluconeogenesis and glucose release in the circulation, thus contributing to fasting hyperglycemia and eventually type 2 diabetes An increase in circulating FFA such as reported in COVID , , , , enhances fatty acid delivery to the liver, which in turn stimulates gluconeogenesis via allosteric regulation of key enzymes or substrate glycerol availability Other mechanisms, more specific to SARS-CoV-2 infection, are reported to contribute to increased gluconeogenesis and subsequent hyperglycemia during COVID Fig.
Recently, 2 novel mechanisms underlying excess endogenous glucose production have been described. First, SARS-CoV-2 infection stimulates glucose production by increasing the activity of phosphoenolpyruvate carboxykinase in primary human hepatocytes The second mechanism involves the Golgi protein GP73 , a type II transmembrane protein located at the luminal surface of the Golgi apparatus that is released in the circulation and regulates intercellular communication during the unfolded protein response Both fasting and a high-fat diet were shown to increase levels of circulating GP73 in mice, which stimulated hepatic gluconeogenesis Similar to fluctuations in nutrient status, SARS-CoV-2 infection promoted GP73 production and secretion in cultured hepatocytes and in mice, inducing hepatocyte glucose production and hyperglycemia in mice, whereas GP73 blockade inhibited SARS-CoVinduced increases in gluconeogenesis in vitro and lowered elevated fasting blood glucose levels in infected mice Elevated circulating levels of GP73 were found in people with COVID, the levels being higher in those with more severe disease and positively correlating with glucose levels Levels of GP73 and glucose remained elevated on hospital discharge, which could indicate that GP73 is implicated in the persistence of hyperglycemia after recovery from COVID Individuals with COVID also feature increased levels of ketone bodies in serum and urine Ketogenesis ie, the production of ketone bodies from acetyl coenzyme A derived from β oxidation of FFA occurs in hepatic mitochondria when glucose availability is low, providing an energy substrate alternative to glucose.
The liver is the only organ that can provide enough ketone bodies to support survival under ketogenic conditions Plasma β-hydroxybutyrate was found to be elevated on hospital admission in individuals with COVID, increased with worsening disease, but decreased within a week during improved clinical disease and on recovery from COVID Increased ketogenesis is not specific for SARS-CoV-2 infection because any critical illness induces catabolism with greater availability of FFA Of note, the ketone body β-hydroxybutyrate was also shown to exert anti-inflammatory and antioxidant effects In this light, increased ketogenesis might be an adaptative mechanism to dampen inflammation and oxidative stress.
In mice infected with murine beta coronavirus A59, a ketogenic diet resulting in mild physiological ketosis prevented infection-induced weight loss and hypoxemia, improved survival, and reduced the expression of the NLRP3 inflammasome and pro-inflammatory cytokines IL-1β, TNFα, IL-6 In line with this, a previous study showed that a high-fat ketogenic diet protects mice against influenza by enhancing antiviral resistance through expansion of protective γδ T cells Preclinical studies also indicate that β-hydroxybutyrate inhibits activation of the NLRP3 inflammasome in isolated hearts and in the macrophages of murine models of systemic inflammatory diseases or Alzheimer disease Nevertheless, studies in humans yielded conflicting results It has been reported that β-hydroxybutyrate enhances the antiviral innate immune response by promoting the secretion of IFN-γ from T cells obtained from individuals with COVID , Levels of β-hydroxybutyrate are higher in individuals with moderate COVID or COVIDrelated ARDS than in healthy individuals, but significantly lower than in individuals with influenza-related ARDS.
These differences were independent of glucose or insulin levels and suggest a blunted ketogenic response to SARS-CoV-2 infection The observed increase in ketogenesis in individuals with COVID , is consistent with an increase in gluconeogenesis.
Oxaloacetate, which is necessary for β-oxidation-derived acetyl-CoA to form citrate and enter the tricarboxylic acid cycle, is used as a precursor of glucose in gluconeogenesis. When availability of oxaloacetate is low, β-oxidation-derived acetyl-CoA cannot enter the tricarboxylic acid cycle and is rerouted to the ketogenic pathway Of note, plasma glucose levels were reported to parallel changes in ketone body levels, with persistent hyperglycemia in people with more severe disease, and normalization of glucose levels in those with favorable outcomes In summary, acute COVID associates with multiple metabolic alterations in the liver, spanning from excessive lipid influx and mitochondrial damage to ER stress causing lipid-accumulation and enhanced gluconeogenesis with increased endogenous glucose production.
Muscular symptoms such as myalgia muscle pain and muscle weakness are also common, both in acute COVID and in PASC A case-control autopsy series demonstrated that skeletal muscle from individuals who had died with COVID had more signs of muscle inflammation and degenerating muscle fibers than people who had died from other causes Individuals with COVID also had significantly greater infiltration of CDpositive leukocytes and CD8-positive T cells, but no evidence of a direct viral infection of myofibers, which is consistent with the findings of another histopathology study Swollen mitochondria and elevation of circulating growth differentiation factor 15 , which is a marker of skeletal muscle bioenergetic dysfunction released from muscle in response to mitochondrial proteotoxic stress and activation of the mitochondrial unfolded protein response , provide evidence of mitochondrial damage in the skeletal muscle of individuals with critical COVID Fatigue or muscle weakness are among the most common long-term symptoms following COVID In muscle biopsies from individuals with persistent muscle symptoms after up to 14 months since recovery from COVID, degenerative alterations including myofiber atrophy were common COVID and the skeletal muscle.
A Effects of acute COVID on skeletal muscle. B Potential consequences of COVID on skeletal muscle. Dashed arrows indicate hypothesized mechanisms. Abbreviations: ACE, angiotensin-converting enzyme 2; ADN, adiponectin; LEP, leptin.
Insulin resistance has been reported in COVID, both during the acute phase and after recovery Table 3. Skeletal muscle is the main site of insulin-stimulated glucose disposal; therefore, muscle insulin resistance has a predominant impact on whole-body glucose metabolism.
Alterations in skeletal muscle mass and physiology play an important role in the insulin resistance leading to dysglycemia during critical illness Acute systemic inflammation during infections profoundly impairs insulin-stimulated whole-body glucose disposal, endogenous glucose production, and glucose oxidation Alterations in cytokine and adipokine profiles such as those described in people with severe COVID , , are known to affect insulin signaling pathways and GLUT4 translocation and to impair insulin-mediated glucose uptake in skeletal muscle Muscle wasting resulting from muscle catabolism for the provision of amino acids as substrates for tissue repair and synthesis of proteins for the immune response is a detrimental consequence of acute inflammation Bed rest also causes muscle loss, mainly because of suppression of muscle protein synthesis , Acute loss of muscle mass during COVID requiring hospitalization is even greater than in other catabolic conditions and impacts short- and long-term clinical outcomes , A substantial loss of muscle mass secondary to muscle disuse results in reduced whole-body glucose utilization , , possibly contributing to hyperglycemia both in acute COVID and after recovery.
The decrease in glucose disposal is paralleled by inhibition of muscle glycogen storage, and by blunted carbohydrate oxidation with longer bed rest, but not by an increase in intramyocellular lipid content.
To the best of our knowledge, no studies have specifically investigated the relationship between muscle mass loss and glucose metabolism in COVID These data suggest an association between a reduction in skeletal muscle mass and impaired glucose metabolism Of note, significant loss of muscle mass and strength ie, sarcopenia during hospitalization associates with failure to return to baseline values at 6 months after discharge, and increased likelihood of PASC symptoms such as fatigue and myalgia COVIDspecific mechanisms such as increased levels of IFN-γ and reduction of ACE2 levels , following SARS-CoV-2 infection could contribute to insulin resistance in skeletal muscle, although specific evidence is lacking.
Virus-induced IFN-γ leads to downregulation of the insulin receptor in skeletal muscle, thus affecting insulin sensitivity Angiotensin , which is generated from angiotensin II by ACE2, has protective effects on skeletal muscle, mainly because of antagonism of the pro-atrophic and pro-fibrotic actions of angiotensin II on muscle Downregulation of ACE2 in COVID leads to decreased angiotensin and increased angiotensin II levels , possibly worsening skeletal muscle damage and loss associated with inflammation and immobilization.
In summary, skeletal muscle damage in COVID appears to be mainly due to immune-inflammatory mechanisms. Mitochondrial damage may contribute to impaired muscle bioenergetics and to the persistence of common PASC symptoms such as fatigue and myalgia Both critical illness and SARS-CoVrelated mechanisms such as an increase in IFN-γ and ACE2 downregulation impair insulin sensitivity in skeletal muscle during COVID Less information is available on the post-recovery phase.
It can be hypothesized that a reduction in muscle mass from acute systemic inflammation, disuse, and possibly malnutrition contributes to persistence of impaired whole-body glucose disposal in some people.
Evidence of pancreatic injury increases in amylase and lipase, and focal enlargement of the pancreas or dilation of the pancreatic duct on computed tomography in people with COVID was reported soon after the beginning of the pandemic The pancreas has been therefore identified as one of the target organs of SARS-CoV-2 Fig.
SARS-CoV-2 viral antigen has been identified in pancreatic islets of autopsy samples from individuals with COVID , , indicating that the virus can directly infect the pancreas. Immunohistochemistry and immunofluorescence of pancreata from persons who died from COVID suggest that SARS-CoV-2 infection of islets induces necroptosis , a form of regulated necrosis mediated by receptor interacting protein kinase-3 and its substrate mixed lineage kinase like , and infiltration of immune cells with local inflammation , Localization of ACE2 in pancreatic islets was demonstrated more than a decade ago, when investigating the pathophysiology of SARS-CoV-associated diabetes Most , —although not all , —studies found evidence of ACE2 or TMPRSS2 expression on pancreatic endocrine cells.
Nonetheless, greater expression of ACE2 has been reported in pancreatic microvascular and ductal structures , It should be noted, however, that SARS-CoV-2 antigens were detected in endothelial, exocrine, and endocrine cells β and non-β cells , independent of ACE2 expression Dipeptidyl-peptidase 4, high-mobility group box 1 protein, transferrin receptor, and NRP1 have been identified as alternative SARS-CoV-2 entry factors, and are expressed in pancreatic islets , , Fig.
COVID and the pancreas. A SARS-CoV-2 entry factors in pancreatic cells; B in vitro effects of SARS-CoV-2 on β cells. C Histopathological and imaging findings in people with COVID Abbreviations: ACE2, angiotensin-converting enzyme 2; DPP4, dipeptidyl-peptidase 4; HMBG1, high-mobility group box 1 protein; NRP1, neuropilin 1; TFRC, transferrin receptor; TMPRSS2, transmembrane protease serine 2.
In vitro, SARS-CoV-2 decreases insulin content and glucose-stimulated insulin secretion of infected islets , , induces loss of β-cell identity and β-cell apoptosis via the c-Jun N-terminal protein kinase MAPK pathway Fig.
In vitro studies indicate that the inflammatory milieu characteristic of COVID contributes to β-cell damage. Exposure of cultured human pancreatic islets to serum obtained from humans hospitalized for COVID with new-onset hyperglycemia or who had recovered from COVID led to islet apoptosis and a dramatic reduction in insulin secretion, which were mediated by proinflammatory cytokines including IL-1β, IL-6, IL, IP, and TNF-α It has also been proposed that transdifferentiation of β cells following SARS-CoV-2 infection leads to lower insulin and greater glucagon production However, a subsequent study failed to confirm that SARS-CoV-2 infection of β cells causes transdifferentiation and indicated only limited, noncytopathic infection, a modest inflammatory response, and minor cellular perturbations, questioning the diabetogenicity of SARS-CoV-2 Overall, most preclinical studies indicate that SARS-CoV-2 has the potential to impair insulin secretion via both direct and indirect β-cell damage.
Although the evidence from autopsy studies indicates that the pancreas can be infected by SARS-CoV-2, the amount of viral RNA in the pancreas is lower than in other tissues , , the direct endocrine cell damage, if any, is mild , , viral persistence in the organ is short , and no histopathology data are available for COVID survivors.
Very few clinical studies have investigated the pathophysiological mechanisms of hyperglycemia in COVID Table 3.
People with COVID had significantly higher levels of plasma C-peptide than controls. Elevated C-peptide and hyperglycemia indicate that β cell function was preserved and insulin resistance is the predominant mechanism underlying hyperglycemia in COVID A more recent but smaller study reinforces these findings: individuals with COVID had hyperglycemia, hyperinsulinemia, and insulin resistance as assessed by HOMA-IR , which was related to an increase in oxidative and nitrosative stress Similarly, higher mean fasting insulin, proinsulin, C peptide levels, homeostasis model assessment of β-cell function, and HOMA-IR have been found in individuals with COVID compared with healthy controls These differences persisted after recovery from COVID The findings of another study showing that C peptide levels were below the lower limit of normal on admission, are somehow in contrast with reports of hyperinsulinemia during COVID Differences could be attributed to different timing of measurements and different disease severity.
Mean C peptide levels returned to normal values at 3 months after discharge and thereafter from 0. A recent study found that, in individuals with severe COVID, inadequate insulin secretion in the face of increased insulin resistance lower disposition index was responsible for hyperglycemia during the acute phase At 6 months after acute COVID, insulin resistance and β-cell function had both improved, and indexes of glucose metabolism were comparable between individuals with or without hyperglycemia during the acute phase.
The response to an oral glucose challenge, however, revealed greater glucose values in the hyperglycemic group. Finally, the results of a small, retrospective study in people with type 2 diabetes who had available data before, during, and after COVID, suggest that insulin resistance is increased during the acute phase of disease and decreases after recovery from COVID, but remains higher compared with baseline Despite some limitations sample size, use of surrogate indices that may be influenced by medications, such as the triglyceride-glucose index, lack of information on the time of follow-up , this study is probably the only one to date that has compared glycemic control in individuals with type 2 diabetes before, during, and after COVID Its results build on previous research , suggesting that perturbations in glucose metabolism persist even after remission.
Of note, SARS-CoV-induced β-cell damage was shown to persist up to 3 years 44 , and alterations in glucose metabolism have been detected in more than half of individuals in a small study with a follow-up of up to 12 years 43 after recovery from acute SARS-CoV infection.
Evidence of endothelitis, microthrombi, and fibrosis in pancreata from people who died from COVID has been reported Nevertheless, the majority of autopsy studies found a low rate of focal pancreatitis or islet degeneration These rates were significantly greater than in non-COVID controls and in people hospitalized for COVID vs those who were not hospitalized.
Whether intrapancreatic ectopic fat is associated with reduced insulin secretion and increased risk of type 2 diabetes is still debated, with some , but not all studies suggesting an association between pancreas steatosis and β-cell function , Further studies should investigate whether pancreas steatosis negatively impacts glucose metabolism in COVID survivors.
Most of the available clinical studies , , , , , indicate that insulin resistance rather than β-cell failure is the main driver of hyperglycemia in COVID During the acute phase, inadequate insulin secretion in the presence of insulin resistance , , likely contributes to the development of hyperglycemia.
This could contribute to diabetic ketoacidosis, which develops when there is an absolute or relative insulin deficiency and—although its incidence is low—is associated with increased mortality in COVID Notably, during diabetic ketoacidosis, insulin resistance was greater in pediatric patients with COVID and preexisting type 1 diabetes compared with those without COVID Establishing whether hyperglycemia during COVID is due, at least in part, to SARS-CoVspecific mechanisms or rather to the inflammatory burden during acute illness ie, stress hyperglycemia is complex.
A study of patients admitted to the intensive care unit with SARS demonstrated that those with COVID had greater alterations in glycemic parameters than those with SARS from other causes However, after adjustment for multiple confounders, glycemic alterations were associated with indicators of disease severity rather than with COVID Stress-induced hyperglycemia during hospital stay is an independent risk factor for post-discharge incident diabetes Similar to reports on COVID 59 , among individuals with newly diagnosed diabetes after stress-induced hyperglycemia the proportion of those with persistent hyperglycemia decreases over time, although as high as two thirds remain hyperglycemic Both impaired β-cell secretory capacity and reduced insulin sensitivity have been implicated in the persistence of impaired glucose metabolism following stress hyperglycemia Pre-existing functional alterations of β cells such as impaired β-cell glucose sensitivity and early-phase insulin secretion could be responsible for the impairment of glucose metabolism rather than β-mass reduction because of SARS-CoV-2 toxicity.
That is, in the presence of an acute event—such as critical illness—people with preexisting, subclinical impairment of β-cell function cannot cope with the sudden increase in insulin demand and develop hyperglycemia.
Consistent with preexisting β-cell dysfunction, people with severe COVID who develop hyperglycemia exhibit a worse glycemic response because of a lower insulinogenic response, dominantly in the early phase 30 minutes of an oral glucose challenge Studies in mice indicate that insulin resistance in skeletal muscle is compensated by hyperinsulinemia when glucose metabolism is normal, but prediabetic mice with insulin resistance caused by diet-induced obesity develop hyperglycemia because of insufficient compensation Consistently, the risk of being diagnosed with type 2 diabetes increases with increasing pre-COVID HbA1c levels HR, 4.
Early administration of dexamethasone improves outcomes in patients with moderate-to-severe non-COVID ARDS and in those with COVID requiring respiratory support However, steroid-induced hyperglycemia is a common downside of steroid treatment in hospitalized individuals that needs to be taken into account.
Glucocorticoids have several detrimental effects on glucose metabolism, including reduced insulin-stimulated activity of the insulin receptor substrate 1-associated phosphoinositide 3-kinase, phosphorylation of insulin-signaling proteins, translocation of the glucose transporter type 4, insulin-stimulated glucose uptake, insulin-stimulated glycogen synthase, and increased glucose production , Steroid use is a predictor of in-hospital 51 and persistent diabetes at 3 months 21 but not 5 months 51 after COVID diagnosis.
In analyses that excluded people who received steroid treatment, the risk of new-onset type 2 diabetes within 6 months of COVID or influenza was still significantly increased in COVID vs influenza, with steroid treatment apparently contributing to diabetes risk only in people with mild disease Table 2 Importantly, in people with less severe COVID ie, receiving no oxygen or simple oxygen , higher doses of corticosteroids were shown to have detrimental consequences and should be avoided The benefits of steroid therapy in people with severe COVID have been clearly demonstrated , and the fear of steroid-induced hyperglycemia should not hold one back from using it.
Previous studies demonstrated that patients with community-acquired pneumonia treated with steroids had higher mean glucose levels and higher blood glucose variability vs patients treated with placebo, but these did not blunt the benefits of steroid therapy in hyperglycemic patients , Similar findings have been reported in people hospitalized for COVID Furthermore, specific guidelines have been developed for the management of people with severe COVID who are started on dexamethasone to ensure proper glucose monitoring and treatment of hyperglycemia The COVID pandemic provides the opportunity to enhance our understanding of how metabolic alterations interact with acute inflammation to trigger immunoinflammatory and further dysregulation of energy metabolism, both during the acute phase and after recovery.
During the acute phase, a strong inflammatory response shifts the metabolism toward catabolic pathways to provide substrates for energy production and support the immune response.
These are mechanisms that have been well described in individuals with sepsis However, SARS-CoV-2 appears to exert specific metabolic effects Fig. Infection of adipose tissue by the virus triggers adipose tissue dysfunction, inducing altered adipokine secretome and lipolysis, leading to an increase in FFA in the circulation that may promote systemic insulin resistance SARS-CoVinduced IFN-γ , and downregulation of ACE2 , may also contribute to the development of systemic insulin resistance.
The increase in circulating FFA, together with SARS-CoVinduced GP73 production , metabolic factors such as MPO , activation of phosphoenolpyruvate carboxykinase , and hyperinsulinemia in response to insulin resistance, stimulate hepatic gluconeogenesis. Thus, hyperglycemia in people with COVID is mainly driven by insulin resistance , , , which may persist even after recovery , , , Preexisting mitochondrial impairment, which is a feature of obesity and type 2 diabetes , might be a key mechanism that aggravates disease severity and contributes to PASC and long-lasting metabolic alterations in these populations.
SARS-CoV-2 infection profoundly impacts mitochondrial structure and function Mitochondria are key not only for energy production, but also for biosynthesis of fatty acids, regulation of cell cycle, apoptosis, innate immune response, and ketogenesis 85 , , Ketogenesis maximizes the production of energy from adipose-tissue-derived fatty acids, supports the immune response, and reduces inflammation Despite increased levels of ketone bodies with increasing COVID severity, an impairment in ketogenesis has been reported , suggesting reduced mitochondrial activity in the liver.
There is also evidence of mitochondrial impairment in other organs, as indicated by elevations in growth differentiation factor 15, a marker of skeletal muscle bioenergetic dysfunction These alterations may persist and underlie PASC Accordingly, low fatty acid oxidation and altered lactate production in skeletal muscle during graded exercise has been reported in COVID survivors, which might contribute to the functional limitation of individuals with PASC Mitochondrial and metabolic alterations are also observed in individuals with critical illness myopathy , where mitochondrial biogenesis, dynamics, as well as fatty acid oxidation and NADH-linked respiration appear to be altered and to contribute to muscle atrophy Normalization of metabolic processes seems to occur in individuals who recover, whereas metabolic derangements persist in those with worsening disease and those who develop PASC.
Other factors, such as changes in body composition resulting from inactivity and changes in food intake a decrease during illness and an increase during recovery impact metabolic health and may lead to persistent alterations, increasing cardiometabolic risk. However, observations that the impact of COVID on glycemic control of patients with type 2 diabetes an increase of 0.
Schematic representation of the effects of SARS-CoV-2 on organs involved in energy metabolism. In adipose tissue, insulin resistance and possibly endothelial dysfunction result in increased lipolysis.
Free fatty acids FFA that are released into the circulation may further worsen insulin resistance and, in the liver, may lead to lipid accumulation and promote hepatic gluconeogenesis, which is also enhanced by hyperinsulinemia secondary to insulin resistance and SARS-CoVinduced Golgi protein 73 GP73 production.
Altered mitochondrial function in the liver may impair fatty acid β oxidation and ketogenesis, which increases with increased COVID severity, but is blunted in comparison to acute respiratory distress syndrome resulting from influenza virus.
Muscle disuse and disease-related malnutrition result in muscle mass loss and further impairment of glucose disposal. Hyperglycemia in patients with COVID may result from these mechanisms, and it is likely that only individuals who are predisposed to impaired glucose metabolism, possibly because of preexisting metabolic dysfunction, will develop long-term hyperglycemia and metabolic dysfunction, with COVID acting as a second hit.
In these persons, especially those who had severe COVID, weight regain with preferential fat catch-up during recovery may further worsen metabolic health, leading to persistent metabolic dysfunction and post-acute sequelae of COVID PASC.
Abbreviations: ACE2, angiotensin-converting enzyme 2; BHB, beta-hydroxybutyrate; FFA, free fatty acids. COVID can directly and indirectly impair energy metabolism, which may persist in some people. Most mechanistic studies only investigated the effect of acute, severe COVID, so that it cannot be excluded that mild and subclinical forms have only minor metabolic effects and consequences.
During the pandemic, particularly during its early phase, an impressive amount of reports have been published, but often lacking rigorous methodology and yielding contradictory or unreliable results. Furthermore, global data sharing and accessibility have been rather limited , which still leaves plenty of room for exploration and consolidation of current knowledge.
Detailed mechanistic studies and longer term follow-up of PASC will tell us whether and to what extent metabolic alterations are persisting or fully reversible.
Several strategies targeting the mechanisms involved in the development of severe disease and PASC appear promising. For example, people with COVID treated with the lipid lowering drugs fibrates showed significantly lower biomarkers of immunoinflammation and faster recovery, with fenofibrate reversing lipid accumulation and blocking SARS-CoV-2 replication in vitro Genetic ablation or pharmacological inhibition of the mitochondrial pyruvate carrier attenuated disease severity in mice with SARS-CoV-2 pneumonia, along with reduced blood glucose and hyperlipidemia following viral pneumonia in obese mice Ketogenic diets have emerged as an effective strategy for weight loss and glycemic control that might also help improve immune function , and thereby represent a promising weight loss strategy in the context of COVID prevention and management.
Regardless of the mechanisms linking COVID and metabolic diseases, the COVID pandemic has a dramatic potential for further rise of the diabetes pandemic.
It is therefore of the utmost importance to perform active screening for metabolic diseases in individuals with a history of COVID, and to further investigate pathomechanisms and targeted treatment strategies for COVIDrelated metabolic diseases.
By this process - known as aerobic glycolysis also called the Warburg effect - only two ATP molecules per molecule of glucose are yielded, compared with a maximum of 36 ATP molecules when glycolysis is coupled to OXPHOS [ 4 , 12 , 14 ].
Although it seems counterintuitive for cells to use a low-efficiency pathway to produce ATP under conditions of high energy demand, it has been proposed that aerobic glycolysis produces the requisite reducing equivalents and biosynthetic substrates that are required for proliferation [ 12 , 14 ].
Activated AKT, also known as protein kinase B, is induced by phosphoinositide 3-kinase PI3K and represents the primary downstream mediator of the metabolic effects of insulin [ 15 ]. AKT increases glucose uptake by stimulating the localization of glucose transporters to the plasma membrane, and it can increase glycolysis by promoting the activities of the rate-limiting glycolytic enzymes hexokinase and phosphofructokinase [ 18 ].
AKT activates mTOR, a key regulator of translation and major effector of cell growth and proliferation, which increases the expression of amino acid transporters [ 19 , 20 ]. mTOR forms two distinct complexes, mTORC1 and mTORC2, respectively. mTORC1 stimulates diverse metabolic pathways, including glycolysis, the oxidative arm of the pentose phosphate pathway, and de novo lipid biosynthesis [ 21 ].
Metabolic pathways in T cells. The switch to glycolysis allows production of the requisite ATP and biosynthetic substrates that are required for proliferation, cytokine synthesis and other T-cell functions. AKT activates mammalian target of rapamycin mTOR , which increases the expression of amino acid transporters and glycolysis.
Inflammation can also lead to hypoxia and reduced nutrient supply. Low ATP levels activate AMP activated protein kinase AMPK , which upregulates catabolic processes, such as fatty acid oxidation, and downregulates anabolic metabolism. AMPK can inhibit mTOR via raptor and lead to cell-cycle arrest. Hypoxia induces hypoxia inducible factor HIF expression via mTOR activity.
HIF-1 forms tertiary complexes with RORγt and p, and enhances inflammation-promoting Th17 cell development through recruitment to the IL promoter or upregulation of glycolysis. Concurrently, HIF-1 attenuates inflammation-restricting regulatory T cell Treg development by binding Foxp3.
HIF-1 induces migration inhibitory factor MIF , which in turn causes HIF-1 expression via the MIF receptor MIF-R in a positive feedback loop. The AMPK stimulator metformin and the mTOR inhibitor rapaymcin are able to augment fatty acid oxidation and can increase Treg generation.
Once activated, these kinases mediate the upregulation of energy-producing catabolic processes, such as fatty acid oxidation and glycolysis, and down-regulate energy-consuming anabolic metabolism [ 22 , 23 ].
The phosphorylation of the mTORC1 component raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress [ 24 ].
There is complex crosstalk between the highly conserved nutrient sensors and the molecular clock of peripheral cells coordinating the circadian control of energy supply on a cellular level [ 25 , 26 ].
Immune cells require energy for housekeeping functions as well as for specific immune functions Table 1. The main housekeeping functions that use significant amounts of ATP are processes of ion transport and macromolecule synthesis.
Specific immune functions include motor functions, antigen processing and presentation, activation and effector functions such as synthesis of antibodies, cytotoxicity, and regulatory functions [ 1 ] Table 1. Calculations show that a quiescent leukocyte needs 1. Activation of quiescent leukocytes leads to an increase of energy expenditure by a factor of 1.
The cellular energy metabolism is relevant to be considered in terms of diseases, for example in cells within the inflamed rheumatoid arthritic joint, because energy supply is limited [ 27 , 28 ]. Secondly, cell accumulation and inflammatory edema increase the distance between cells and oxygen-supplying arterial vessels.
Thirdly, vasodilatation, as induced by inflammatory mediators such as prostaglandin E 2 , lowers blood flow and thus the supply of oxygen and nutrients is reduced such as glucose and amino acids as well as the removal of metabolic waste such as lactate and carbon dioxide [ 27 , 28 ].
Furthermore, specific T-cell functions such as cytokine production and proliferation are unaffected in glucose-containing medium, even under complete OXPHOS suppression. Only when glucose is also absent are these functions significantly decreased [ 29 ].
These observations support the view of hypoxia being a key driving factor in chronic inflammation. The first data indicating the hypoxic nature of the rheumatoid arthritis RA synovium were achieved in the s by measuring oxygen tension by means of a Clark-type electrode in samples of synovial fluids of patients with RA [ 28 , 30 , 31 ].
Hypoxia has been demonstrated in patients with RA undergoing surgery for tendon rupture by Sivakumar and colleagues [ 32 ]. Just recently, by means of a novel oxygen-sensing probe in vivo , even a direct relationship between tissue partial pressure of oxygen levels and joint inflammation specifically T-cell and macrophage infiltrates and proinflammatory cytokine expression could be demonstrated for the first time [ 33 ], and it was shown that hypoxia can be reversed by antiinflammatory treatment [ 34 ].
One principal regulator of the adaptive response to hypoxia is the transcription factor hypoxia inducible factor HIF -1 [ 28 , 35 ]. HIF-1 is a heterodimeric protein that consists of an oxygen-sensitive α subunit and a constitutively expressed β subunit [ 28 , 36 ].
In nonhypoxic cells, HIF-1α is continuously tagged by oxygen-dependent hydroxylation and in this way targeted for proteasomal degradation [ 28 , 36 ].
Under hypoxic conditions, however, HIF-1 is stabilized. HIF target genes promote erythropoiesis, angiogenesis and vasodilatation, and HIF is a master switch to a glycolytic cell metabolism, resolving and counteracting hypoxic conditions [ 28 ].
Several findings indicate that HIF is involved in the persistence of inflammation and progression of neovascularization during RA. HIF is abundantly expressed in the arthritic tissue [ 38 ]. Deletion of HIF in macrophages and neutrophils resulted in a complete loss of the inflammatory response [ 39 ].
Hypoxia might also play a central role in pathogenesis of systemic sclerosis by augmenting vascular disease and tissue fibrosis [ 40 , 41 ].
However, HIF-1 was found to be decreased in the epidermis of systemic sclerosis patients compared with healthy controls [ 42 ], perhaps due to an increased prolyl-hydroxylase activity resulting in faster degradation of HIF-1 [ 41 ]. Hypoxia, and specifically HIF-1, is a potent and rapid inducer of MIF.
MIF is also able to counter-regulate glucocorticoid-mediated suppression of MIF and HIF-1α expression [ 36 ]. Targeting MIF and HIF may thus be effective in disrupting self-maintaining inflammation.
The differentiation of naïve CD4 cells into Th1 and Th17 subsets of T-helper cells is selectively regulated by signaling from mTORC1 that is dependent on the small GTPase Rheb [ 43 ].
Th1, Th2 and Th17 cells express high surface levels of the glucose transporter- Glut1 and switch on a highly glycolytic program. In contrast, regulatory T cells Tregs express low levels of Glut1 and have high lipid oxidation rates [ 44 ].
In an asthma model, AMPK stimulation was sufficient to decrease Glut1 and increase Treg generation, indicating that the distinct metabolic programs can be modulated in vivo [ 44 ]. Recently, persistent hypoxia and glycolysis were demonstrated to control the balance between inflammation-promoting Th17 cells and inflammation-restricting Tregs [ 9 , 45 ].
Hypoxia-induced HIF expression exerts a direct transcriptional activation of RORγt, a master regulator of Th17 cell differentiation, and recruitment to the IL promoter via tertiary complex formation with RORγt and p Figure 1 [ 9 , 45 ].
Concurrently, HIF-1 attenuates induced Treg development by binding Foxp3, a key transcription factor that promotes the Treg lineage, via a proposed ubiquitination pathway [ 9 , 45 ]. Mice with HIF-1α-deficient T cells are resistant to induction of Thdependent experimental autoimmune encephalitis, associated with diminished Th17 cells and increased Tregs, indicating the therapeutic potential of HIF modulation.
Similar to these findings, another study suggested that HIF-1α is involved in differentiation of Th17 cells and Tregs, but ascribed the role of HIF-1a to upregulation of glycolysis and not as a direct effect of HIF-1a on RORγt and Foxp3 [ 9 , 46 ].
Tumor hypoxia appears to be different, as it has been reported to inhibit T-cell proliferation and cytokine secretion and to activate Tregs [ 48 ]. Glycolysis has been suggested to play a role in the pathogenesis of RA [ 49 ]. The activity levels of two major enzymes of the glycolytic pathway - glyceraldehyde 3-phosphate dehydrogenase and lactate dehydrogenase - were increased in RA synovial cells [ 50 ].
However, clear studies of a direct relationship of increased glycolytic activity and inflammation are lacking. It is striking that several glycolytic enzymes such as glucosephosphate isomerase, enolase, aldolase and triose phosphate isomerase act as autoantigens [ 49 ]; however, their role in RA remains unclear [ 49 , 51 , 52 ].
Rapamycin also known as sirolimus is an mTOR inhibitor used in transplantation medicine. This inhibitor acts similar to the immunosuppressant FK tacrolimus by binding to the intracellular immunophilin FK-binding protein 12 FKBP Unlike the FKFKBP12 complex that inhibits calcineurin, however, the rapamycin-FKBP12 complex interferes with the function of mTOR.
Rapamycin has been found effective for systemic lupus erythematosus and systemic sclerosis in animal models and pilot clinical trials [ 53 — 57 ].
Tregs can be expanded by rapamycin in vitro [ 58 ] and were found to suppress colitis in an experimental mouse model [ 59 ]. Treatment of mice after infection with either the mTOR inhibitor rapaymcin or the AMPK stimulator metformin, two drugs that augment fatty acid oxidation, enhanced the development of memory CD8 T cells [ 6 , 60 , 61 ].
Similar to T cells, dendritic cells were recently shown upon activation by Toll-like receptors to switch from oxidative phosphorylation to glycolysis [ 62 ]. Activation of macrophages by IFNγ and lipopolysaccharide inhibits mitochondrial respiration by release of large quantities of nitric oxide produced by the inducible nitric oxide synthase [ 65 ].
Furthermore, monocytes begin to acquire a glycolytic metabolism during differentiation into macrophages, with possible significance for the ability of tissue macrophages to adapt to hypoxia [ 66 ]. Prolongation of survival by hypoxia has also been found for human neutrophils [ 67 , 68 ].
NOD-like receptors are involved in the recognition of host-derived and microbial danger-associated molecules that lead to the assembly of high-molecular-mass complexes called inflammasomes and the subsequent generation- of active caspase 1, a requisite for the production of the inflammatory cytokine IL-1β [ 7 ].
Recently, the NLRP3 inflammasome has been shown to cause insulin resistance in the periphery and may be important for the pathogenesis of type 2 diabetes [ 7 , 69 ]. In contrast to metabolic changes, which occur locally in cells and tissue - for example, due to hypoxia at the site of inflammation - interesting metabolic changes can also occur systemically.
Circulating peripheral blood cells, such as T cells, display oxidative stress due to depletion of glutathione in systemic lupus erythematosus [ 70 ]. Levels of surface thiols and intracellular glutathione of leukocytes are significantly lower in RA patients [ 71 ].
Excessive production of reactive oxygen species disturbs the redox status and can modulate the expression of inflammatory chemokines, leading to inflammatory processes [ 72 ]. Such differences in metabolism may represent a clear distinction between localized and systemic autoimmune inflammatory diseases.
Energy metabolism is not only a question for a single cell or a group of cells such as, for example, T cells or muscle cells, because provision and allocation of energy-rich fuels involves the entire body. Need for energy-rich substrates at a certain location in the body can induce a systemic response if local stores are not sufficient to provide necessary supplies.
The systemic response redirects energy-rich fuels from stores to the site of action, the consumers [ 2 ]. Such a redirection program can be started by a voluntary act when an individual decides to use muscles during exercise. In such a situation, the central nervous system activates, among others, the sympathetic nervous system adrenaline, noradrenaline , the hypothalamic-pituitary-adrenal axis cortisol , and the hypothalamic-pituitary-somatic axis growth hormone, insulin-like growth factor-1 , which induce gluconeogenesis,- glycogenolysis, and lipolysis.
This is supported by release of IL-6 from muscles into systemic circulation, which helps activate the redirection program [ 73 ]. Redirection of energy-rich substrates from storage sites to consumer can be called the energy appeal reaction. If the immune system needs energy-rich fuels in the context of infection or other forms of activation, a similar energy appeal reaction is prompted [ 2 ].
The response is a concerted action of the neuroendocrine immune network. But does the activated immune system need a lot of energy?
Table 2 presents the energy demand of the entire body, systems, and organs. Obviously, the immune system needs a lot of energy, particularly in an activated state. In an inflammatory situation, the energy appeal reaction is driven by cytokine-induced stimulation of the central nervous system, endocrine organs, and energy storage organs such as the liver, muscles, and fat tissue [ 2 ].
IL-6 is a classical candidate that can activate these remote places but also IFNγ, IFNα, IL-2, TNF, and others [ 2 ]. The question remains whether this seemingly adaptive program has been positively selected in the context of CIDs such as RA or systemic lupus erythematosus.
The evolutionary principle of replication with variation and selection is undeniably fundamental and has history. This is a successful history of positive selection, which can only happen under circumstances of unrestricted gene transfer to offspring.
The hypothesis is that genes which play a specific role in CIDs were not positively and specifically selected for a CID because unrestricted gene transfer was not possible in CIDs [ 2 , 74 ].
If this is correct, regulatory mechanisms of the neuroendocrine immune network did not evolve to cope with CIDs. Instead, the neuroendocrine immune network was positively selected in the context of nonlife-threatening transient inflammatory episodes such as, for example, infection or wound healing.
These episodes are usually short lived and do not last longer than 3 to 6 weeks. No prolonged adaptive program specifically exists for CIDs. Similarly, the abovementioned energy appeal reaction as a consequence of systemic cytokine stimulation has been positively selected for transient nonlife-threatening inflammatory episodes [ 2 , 74 ].
Furthermore, genes that are associated with CIDs have been positively selected independent of CIDs. The theory of antagonistic pleiotropy - formulated by Williams in the s - similarly applies to CIDs [ 2 , 75 ].
This theory suggests that genes associated with CIDs have been positively selected to improve survival at younger ages and to stimulate reproduction independent of CIDs. Recent delineation shows that several CID risk genes have a pleiotropic meaning outside CIDs at younger ages [ 76 ].
Organisms evolved under conditions that favored the development of complex mechanisms for obtaining food and for storage and allocation of energy-rich fuels. Energy regulation and cellular bioenergetics take the highest position in the hierarchy of homeostatic control.
We can call them storing factors. In contrast, provision of energy-rich fuels to the entire body in the form of glucose, protein, and fatty acids is mainly supported by mediator substances of the sympathetic nervous system, the hypothalamic-pituitary-hormonal axes cortisol and growth hormone , and the pancreas glucagon.
We can call them provision factors. Table 3 describes particular aspects of the neuroendocrine immune response linking it to the energy appeal reaction. The energy appeal reaction is not an unspecific fight-or-flight response in the sense of Hans Selye, but an adaptive program.
If the adaptive program is used too long, real problems can appear that are a consequence of worn-out regulation. That exhausted regulation really exists is substantiated by the fact that patients on ICUs with severe activation of the stress system sometimes suffer from lifelong adrenal insufficiency even after overall recovery [ 77 ].
A longstanding reallocation program can thus lead to acute and chronic disease sequelae as mentioned in Table 3. The framework explains that CID sequelae are a consequence of a continuous energy appeal reaction. The systemic response of the body - the energy appeal reaction - is important to support the immune system during short-lived inflammatory episodes, but its continuous use in CIDs is highly unfavorable.
Since disease sequelae are a significant part of clinical CID, etiology of disease sequelae is also part of CID etiology. It becomes understandable that long-term changes of the neuroendocrine immune network as a consequence of a chronic energy appeal reaction are also part of etiological considerations.
We conclude that among genetic issues, environmental factors microbes, toxins, drugs, injuries, radiation, cultural background, and geography , exaggerated immune and wound responses, and irrecoverable tissue destruction, changes of the neuroendocrine immune network in the context of a prolonged energy appeal reaction become a fifth factor of CID etiology [ 78 ].
Metabolic pathways drive an energy appeal reaction for the immune response on cellular and organism levels. However, if the immune response is not sufficient to resolve inflammation, the metabolic programs can support ongoing chronic inflammation and lead to metabolic disease sequelae.
This suggests chronic inflammation to be powered by energy metabolism, indicating that energy metabolism is a promising therapeutic target. Buttgereit F, Burmester GR, Brand MD: Bioenergetics of immune functions: fundamental and therapeutic aspects.
Immunol Today. Article CAS PubMed Google Scholar. Straub RH, Cutolo M, Buttgereit F, Pongratz G: Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med. Energy metabolism disorders are characterized by ATP deficits and reactive oxygen species increase.
Oxygen and mitochondria are essential for ATP production, hypoxia and mitochondrial dysfunction both affect the energy production process. Renin-angiotensin and adenine signaling pathway also play important regulatory roles in energy metabolism. In addition, disturbance of energy metabolism is a key factor in the development of hereditary nephropathy such as autosomal dominant polycystic kidney disease.
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Concurrently, HIF-1 attenuates chronnic regulatory T an Treg development by binding Foxp3. HIF-1 induces migration inhibitory Pre-workout meal ideas MIFwhich diseqses turn causes HIF-1 expression metaboolism the MIF receptor Diseqses in a Diseasew feedback loop.
The AMPK stimulator metformin and the Energy metabolism and chronic diseases Enefgy rapaymcin are able to augment fatty acid oxidation and can increase Treg generation. Once activated, these kinases mediate the upregulation of energy-producing catabolic processes, such as fatty acid oxidation and glycolysis, and down-regulate energy-consuming anabolic metabolism [ 2223 ].
The phosphorylation of the mTORC1 component raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress [ 24 ]. There is complex crosstalk between the highly conserved nutrient sensors and the molecular clock of peripheral cells coordinating the circadian control of energy supply on a cellular level [ 2526 ].
Immune cells require energy for housekeeping functions as well as for specific immune functions Table 1. The main housekeeping functions that use significant amounts of ATP are processes of ion transport and macromolecule synthesis. Specific immune functions include motor functions, antigen processing and presentation, activation and effector functions such as synthesis of antibodies, cytotoxicity, and regulatory functions [ 1 ] Table 1.
Calculations show that a quiescent leukocyte needs 1. Activation of quiescent leukocytes leads to an increase of energy expenditure by a factor of 1. The cellular energy metabolism is relevant to be considered in terms of diseases, for example in cells within the inflamed rheumatoid arthritic joint, because energy supply is limited [ 2728 ].
Secondly, cell accumulation and inflammatory edema increase the distance between cells and oxygen-supplying arterial vessels. Thirdly, vasodilatation, as induced by inflammatory mediators such as prostaglandin E 2lowers blood flow and thus the supply of oxygen and nutrients is reduced such as glucose and amino acids as well as the removal of metabolic waste such as lactate and carbon dioxide [ 2728 ].
Furthermore, specific T-cell functions such as cytokine production and proliferation are unaffected in glucose-containing medium, even under complete OXPHOS suppression. Only when glucose is also absent are these functions significantly decreased [ 29 ]. These observations support the view of hypoxia being a key driving factor in chronic inflammation.
The first data indicating the hypoxic nature of the rheumatoid arthritis RA synovium were achieved in the s by measuring oxygen tension by means of a Clark-type electrode in samples of synovial fluids of patients with RA [ 283031 ].
Hypoxia has been demonstrated in patients with RA undergoing surgery for tendon rupture by Sivakumar and colleagues [ 32 ]. Just recently, by means of a novel oxygen-sensing probe in vivoeven a direct relationship between tissue partial pressure of oxygen levels and joint inflammation specifically T-cell and macrophage infiltrates and proinflammatory cytokine expression could be demonstrated for the first time [ 33 ], and it was shown that hypoxia can be reversed by antiinflammatory treatment [ 34 ].
One principal regulator of the adaptive response to hypoxia is the transcription factor hypoxia inducible factor HIF -1 [ 2835 ]. HIF-1 is a heterodimeric protein that consists of an oxygen-sensitive α subunit and a constitutively expressed β subunit [ 2836 ].
In nonhypoxic cells, HIF-1α is continuously tagged by oxygen-dependent hydroxylation and in this way targeted for proteasomal degradation [ 2836 ]. Under hypoxic conditions, however, HIF-1 is stabilized.
HIF target genes promote erythropoiesis, angiogenesis and vasodilatation, and HIF is a master switch to a glycolytic cell metabolism, resolving and counteracting hypoxic conditions [ 28 ]. Several findings indicate that HIF is involved in the persistence of inflammation and progression of neovascularization during RA.
HIF is abundantly expressed in the arthritic tissue [ 38 ]. Deletion of HIF in macrophages and neutrophils resulted in a complete loss of the inflammatory response [ 39 ].
Hypoxia might also play a central role in pathogenesis of systemic sclerosis by augmenting vascular disease and tissue fibrosis [ 4041 ]. However, HIF-1 was found to be decreased in the epidermis of systemic sclerosis patients compared with healthy controls [ 42 ], perhaps due to an increased prolyl-hydroxylase activity resulting in faster degradation of HIF-1 [ 41 ].
Hypoxia, and specifically HIF-1, is a potent and rapid inducer of MIF. MIF is also able to counter-regulate glucocorticoid-mediated suppression of MIF and HIF-1α expression [ 36 ]. Targeting MIF and HIF may thus be effective in disrupting self-maintaining inflammation. The differentiation of naïve CD4 cells into Th1 and Th17 subsets of T-helper cells is selectively regulated by signaling from mTORC1 that is dependent on the small GTPase Rheb [ 43 ].
Th1, Th2 and Th17 cells express high surface levels of the glucose transporter- Glut1 and switch on a highly glycolytic program. In contrast, regulatory T cells Tregs express low levels of Glut1 and have high lipid oxidation rates [ 44 ].
In an asthma model, AMPK stimulation was sufficient to decrease Glut1 and increase Treg generation, indicating that the distinct metabolic programs can be modulated in vivo [ 44 ]. Recently, persistent hypoxia and glycolysis were demonstrated to control the balance between inflammation-promoting Th17 cells and inflammation-restricting Tregs [ 945 ].
Hypoxia-induced HIF expression exerts a direct transcriptional activation of RORγt, a master regulator of Th17 cell differentiation, and recruitment to the IL promoter via tertiary complex formation with RORγt and p Figure 1 [ 945 ].
Concurrently, HIF-1 attenuates induced Treg development by binding Foxp3, a key transcription factor that promotes the Treg lineage, via a proposed ubiquitination pathway [ 945 ].
Mice with HIF-1α-deficient T cells are resistant to induction of Thdependent experimental autoimmune encephalitis, associated with diminished Th17 cells and increased Tregs, indicating the therapeutic potential of HIF modulation.
Similar to these findings, another study suggested that HIF-1α is involved in differentiation of Th17 cells and Tregs, but ascribed the role of HIF-1a to upregulation of glycolysis and not as a direct effect of HIF-1a on RORγt and Foxp3 [ 946 ].
Tumor hypoxia appears to be different, as it has been reported to inhibit T-cell proliferation and cytokine secretion and to activate Tregs [ 48 ]. Glycolysis has been suggested to play a role in the pathogenesis of RA [ 49 ].
The activity levels of two major enzymes of the glycolytic pathway - glyceraldehyde 3-phosphate dehydrogenase and lactate dehydrogenase - were increased in RA synovial cells [ 50 ]. However, clear studies of a direct relationship of increased glycolytic activity and inflammation are lacking.
It is striking that several glycolytic enzymes such as glucosephosphate isomerase, enolase, aldolase and triose phosphate isomerase act as autoantigens [ 49 ]; however, their role in RA remains unclear [ 495152 ].
Rapamycin also known as sirolimus is an mTOR inhibitor used in transplantation medicine. This inhibitor acts similar to the immunosuppressant FK tacrolimus by binding to the intracellular immunophilin FK-binding protein 12 FKBP Unlike the FKFKBP12 complex that inhibits calcineurin, however, the rapamycin-FKBP12 complex interferes with the function of mTOR.
Rapamycin has been found effective for systemic lupus erythematosus and systemic sclerosis in animal models and pilot clinical trials [ 53 — 57 ]. Tregs can be expanded by rapamycin in vitro [ 58 ] and were found to suppress colitis in an experimental mouse model [ 59 ].
Treatment of mice after infection with either the mTOR inhibitor rapaymcin or the AMPK stimulator metformin, two drugs that augment fatty acid oxidation, enhanced the development of memory CD8 T cells [ 66061 ]. Similar to T cells, dendritic cells were recently shown upon activation by Toll-like receptors to switch from oxidative phosphorylation to glycolysis [ 62 ].
Activation of macrophages by IFNγ and lipopolysaccharide inhibits mitochondrial respiration by release of large quantities of nitric oxide produced by the inducible nitric oxide synthase [ 65 ].
Furthermore, monocytes begin to acquire a glycolytic metabolism during differentiation into macrophages, with possible significance for the ability of tissue macrophages to adapt to hypoxia [ 66 ].
Prolongation of survival by hypoxia has also been found for human neutrophils [ 6768 ]. NOD-like receptors are involved in the recognition of host-derived and microbial danger-associated molecules that lead to the assembly of high-molecular-mass complexes called inflammasomes and the subsequent generation- of active caspase 1, a requisite for the production of the inflammatory cytokine IL-1β [ 7 ].
Recently, the NLRP3 inflammasome has been shown to cause insulin resistance in the periphery and may be important for the pathogenesis of type 2 diabetes [ 769 ]. In contrast to metabolic changes, which occur locally in cells and tissue - for example, due to hypoxia at the site of inflammation - interesting metabolic changes can also occur systemically.
Circulating peripheral blood cells, such as T cells, display oxidative stress due to depletion of glutathione in systemic lupus erythematosus [ 70 ]. Levels of surface thiols and intracellular glutathione of leukocytes are significantly lower in RA patients [ 71 ]. Excessive production of reactive oxygen species disturbs the redox status and can modulate the expression of inflammatory chemokines, leading to inflammatory processes [ 72 ].
Such differences in metabolism may represent a clear distinction between localized and systemic autoimmune inflammatory diseases. Energy metabolism is not only a question for a single cell or a group of cells such as, for example, T cells or muscle cells, because provision and allocation of energy-rich fuels involves the entire body.
Need for energy-rich substrates at a certain location in the body can induce a systemic response if local stores are not sufficient to provide necessary supplies. The systemic response redirects energy-rich fuels from stores to the site of action, the consumers [ 2 ].
Such a redirection program can be started by a voluntary act when an individual decides to use muscles during exercise.
: Energy metabolism and chronic diseases| About this Special Issue | HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry. Concurrently, HIF-1 attenuates inflammation-restricting regulatory T cell Treg development by binding Foxp3. Uddin GM, Zhang L, Shah S, Fukushima A, Wagg CS, Gopal K, et al. The latter, however, was a strong predictor of in-hospital diabetes HR, 1. Frangogiannis NG. Jones RG, Thompson CB: Revving the engine: signal transduction fuels T cell activation. Chen M, Gao C, Yu J, Ren S, Wang M, Wynn RM, et al. |
| Government of Canada navigation bar | All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Bloom MW, Greenberg B, Jaarsma T, Januzzi JL, Lam CSP, Maggioni AP, et al. Heart failure with reduced ejection fraction. Nat Rev Dis Primers. doi: CrossRef Full Text Google Scholar. Conrad N, Judge A, Tran J, Mohseni H, Hedgecott D, Crespillo AP, et al. Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. PubMed Abstract CrossRef Full Text Google Scholar. Hao G, Wang X, Chen Z, Zhang L, Zhang Y, Wei B, et al. Prevalence of heart failure and left ventricular dysfunction in China: the China hypertension survey, Eur J Heart Failure. Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol. Nadrowski P, Chudek J, Grodzicki T, Mossakowska M, Skrzypek M, Wiecek A, et al. Plasma level of N-terminal pro brain natriuretic peptide NT-proBNP in elderly population in poland—the polsenior study. Exp Gerontol. Triposkiadis F, Giamouzis G, Parissis J, Starling RC, Boudoulas H, Skoularigis J, et al. Reframing the association and significance of co-morbidities in heart failure. von Haehling S. Co-morbidities in heart failure beginning to sprout-and no end in sight? Khan MS, Samman Tahhan A, Vaduganathan M, Greene SJ, Alrohaibani A, Anker SD, et al. Trends in prevalence of comorbidities in heart failure clinical trials. White JR, Chang CC, So-Armah KA, Stewart JC, Gupta SK, Butt AA, et al. Depression and human immunodeficiency virus infection are risk factors for incident heart failure among veterans: veterans aging cohort study. Yusuf S, Joseph P, Rangarajan S, Islam S, Mente A, Hystad P, et al. Modifiable risk factors, cardiovascular disease, and mortality in individuals from 21 high-income, middle-income, and low-income countries PURE : a prospective cohort study. Sbolli M, Fiuzat M, Cani D, O'Connor CM. Depression and heart failure: the lonely comorbidity. Drager LF, McEvoy RD, Barbe F, Lorenzi-Filho G, Redline S. Sleep apnea and cardiovascular disease: lessons from recent trials and need for team science. Takada S, Sabe H, Kinugawa S. Abnormalities of skeletal muscle, adipocyte tissue, and lipid metabolism in heart failure: practical therapeutic targets. Front Cardiovasc Med. Suzuki K, Claggett B, Minamisawa M, Packer M, Zile MR, Rouleau J, et al. Tromp J, Tay WT, Ouwerkerk W, Teng TK, Yap J, MacDonald MR, et al. Multimorbidity in patients with heart failure from 11 asian regions: a prospective cohort study using the ASIAN-HF registry. PLoS Med. Neubauer S. The failing heart—an engine out of fuel. N Engl J Med. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. Bertero E, Maack C. Metabolic remodelling in heart failure. Nickel A, Löffler J, Maack C. Myocardial energetics in heart failure. Basic Res Cardiol. Gibb AA, Hill BG. Metabolic coordination of physiological and pathological cardiac remodeling. Circ Res. Noordali H, Loudon BL, Frenneaux MP, Madhani M. Cardiac metabolism - a promising therapeutic target for heart failure. Pharmacol Ther. Arumugam S, Sreedhar R, Thandavarayan RA, Karuppagounder V, Watanabe K. Targeting fatty acid metabolism in heart failure: is it a suitable therapeutic approach? Drug discovery today. Birkenfeld AL, Jordan J, Dworak M, Merkel T, Burnstock G. Myocardial metabolism in heart failure: purinergic signalling and other metabolic concepts. Nguyen TD, Schulze PC. Lipid in the midst of metabolic remodeling - therapeutic implications for the failing heart. Adv Drug Deliv Rev. Carley AN, Lewandowski ED. Triacylglycerol turnover in the failing heart. Biochim Bio Acta. Son NH, Yu S, Tuinei J, Arai K, Hamai H, Homma S, et al. PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation. J Clin Invest. Kohlhaas M, Nickel AG, Maack C. Mitochondrial energetics and calcium coupling in the heart. J Physiol. Murashige D, Jang C, Neinast M, Edwards JJ, Cowan A, Hyman MC, et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Selvaraj S, Kelly DP, Margulies KB. Implications of altered ketone metabolism and therapeutic ketosis in heart failure. D'Antona G, Ragni M, Cardile A, Tedesco L, Dossena M, Bruttini F, et al. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metab. Toneto AT, Ferreira Ramos LA, Salomão EM, Tomasin R, Aereas MA, Gomes-Marcondes MC. Nutritional leucine supplementation attenuates cardiac failure in tumour-bearing cachectic animals. J Cach Sarco Muscle. Fidale TM, Antunes HKM, Alex Dos Santos L, Rodrigues de Souza F, Deconte SR, Borges Rosa de Moura F, et al. Increased dietary leucine reduces doxorubicin-associated cardiac dysfunction in rats. Front Physiol. Sun H, Wang Y. Branched chain amino acid metabolic reprogramming in heart failure. Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. Uddin GM, Zhang L, Shah S, Fukushima A, Wagg CS, Gopal K, et al. Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure. Cardiovasc Diabetol. Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, et al. Catabolic defect of branched-chain amino acids promotes heart failure. Chen M, Gao C, Yu J, Ren S, Wang M, Wynn RM, et al. Therapeutic effect of targeting branched-chain amino acid catabolic flux in pressure-overload induced heart failure. J Am Heart Asso. Aksentijević D, Karlstaedt A, Basalay MV, O'Brien BA, Sanchez-Tatay D, Eminaga S, et al. Intracellular sodium elevation reprograms cardiac metabolism. Nat Commun. Mullens W, Verbrugge FH, Nijst P, Tang WHW. Renal sodium avidity in heart failure: from pathophysiology to treatment strategies. Eur Heart J. Baartscheer A, Schumacher CA, van Borren MM, Belterman CN, Coronel R, Fiolet JW. Cardiovasc Res. Eisner DA, Caldwell JL, Trafford AW, Hutchings DC. The control of diastolic calcium in the heart: basic mechanisms and functional implications. Boyman L, Karbowski M, Lederer WJ. Trends Mol Med. Dridi H, Kushnir A, Zalk R, Yuan Q, Melville Z, Marks AR. Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target. Ruiz-Meana M, Minguet M, Bou-Teen D, Miro-Casas E, Castans C, Castellano J, et al. Ryanodine receptor glycation favors mitochondrial damage in the senescent heart. Calcium signaling and reactive oxygen species in mitochondria. Zhang J, Abel ED. Effective metabolic approaches for the energy starved failing heart: bioenergetic resiliency via redundancy or something else? Ardehali H, Sabbah HN, Burke MA, Sarma S, Liu PP, Cleland JG, et al. Targeting myocardial substrate metabolism in heart failure: potential for new therapies. Eur J Heart Fail. Chen Z, Liu M, Li L, Chen L. Involvement of the Warburg effect in non-tumor diseases processes. J Cell Physiol. Briasoulis A, Androulakis E, Christophides T, Tousoulis D. The role of inflammation and cell death in the pathogenesis, progression and treatment of heart failure. Heart Fail Rev. Chow SL, Maisel AS, Anand I, Bozkurt B, de Boer RA, Felker GM, et al. Role of biomarkers for the prevention, assessment, and management of heart failure: a scientific statement from the American heart association. Emdin M, Aimo A, Vergaro G, Bayes-Genis A, Lupón J, Latini R, et al. sST2 predicts outcome in chronic heart failure beyond NT-proBNP and high-sensitivity troponin T. J Am Coll Cardiol. Martini E, Kunderfranco P, Peano C, Carullo P, Cremonesi M, Schorn T, et al. Single-cell sequencing of mouse heart immune infiltrate in pressure overload-driven heart failure reveals extent of immune activation. Abplanalp WT, Cremer S, John D, Hoffmann J, Schuhmacher B, Merten M, et al. Clonal hematopoiesis-driver DNMT3A mutations alter immune cells in heart failure. Adamo L, Rocha-Resende C, Prabhu SD, Mann DL. Reappraising the role of inflammation in heart failure. Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Chen D, Assad-Kottner C, Orrego C, Torre-Amione G. Cytokines and acute heart failure. Crit Care Med. Lin HB, Naito K, Oh Y, Farber G, Kanaan G, Valaperti A, et al. McMaster WG, Kirabo A, Madhur MS, Harrison DG. Inflammation, immunity, and hypertensive end-organ damage. Sanada S, Hakuno D, Higgins LJ, Schreiter ER, McKenzie AN, Lee RT. IL and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. Paulus WJ. Unfolding discoveries in heart failure. Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. The extracellular matrix in ischemic and nonischemic heart failure. Brakenhielm E, González A, Díez J. Role of cardiac lymphatics in myocardial edema and fibrosis: JACC review topic of the week. Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K, et al. Role of left ventricular stiffness in heart failure with normal ejection fraction. Ling LH, Kistler PM, Kalman JM, Schilling RJ, Hunter RJ. Comorbidity of atrial fibrillation and heart failure. van den Berg MP, Mulder BA, Klaassen SHC, Maass AH, van Veldhuisen DJ, van der Meer P, et al. Heart failure with preserved ejection fraction, atrial fibrillation, and the role of senile amyloidosis. Santhanakrishnan R, Wang N, Larson MG, Magnani JW, McManus DD, Lubitz SA, et al. Atrial fibrillation begets heart failure and vice versa: temporal associations and differences in preserved versus reduced ejection fraction. Wong JA, Conen D, Van Gelder IC, McIntyre WF, Crijns HJ, Wang J, et al. Progression of device-detected subclinical atrial fibrillation and the risk of heart failure. Patel RB, Vaduganathan M, Shah SJ, Butler J. Atrial fibrillation in heart failure with preserved ejection fraction: insights into mechanisms and therapeutics. Yoo S, Aistrup G, Shiferaw Y, Ng J, Mohler PJ, Hund TJ, et al. Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure. JCI Insight. Kutyifa V, Vermilye K, Solomon SD, McNitt S, Moss AJ, Daimee UA. Long-term outcomes of cardiac resynchronization therapy by left ventricular ejection fraction. Wijesurendra RS, Casadei B. Mechanisms of atrial fibrillation. Ballou LM, Lin RZ, Cohen IS. Control of cardiac repolarization by phosphoinositide 3-kinase signaling to ion channels. Seferović PM, Petrie MC, Filippatos GS, Anker SD, Rosano G, Bauersachs J, et al. Type 2 diabetes mellitus and heart failure: a position statement from the heart failure association of the European society of cardiology. Euro J Heart Fail. Greene SJ, Vaduganathan M, Khan MS, Bakris GL, Weir MR, Seltzer JH, et al. Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes. Rørth R, Jhund PS, Mogensen UM, Kristensen SL, Petrie MC, Køber L, et al. Risk of incident heart failure in patients with diabetes and asymptomatic left ventricular systolic dysfunction. Diab Care. Rawshani A, Rawshani A, Sattar N, Franzén S, McGuire DK, Eliasson B, et al. Relative prognostic importance and optimal levels of risk factors for mortality and cardiovascular outcomes in type 1 diabetes mellitus. Dillmann WH. Diabetic cardiomyopathy. Taqueti VR, Di Carli MF. Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review. Riehle C, Abel ED. Insulin signaling and heart failure. Donath MY, Meier DT, Boni-Schnetzler M. Inflammation in the pathophysiology and therapy of cardiometabolic disease. Endocr Rev. Fernandez-Ruiz I. A new link for heart failure and diabetes. Papadaki M, Holewinski RJ, Previs SB, Martin TG, Stachowski MJ, Li A, et al. Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function. Kenny HC, Abel ED. Heart failure in type 2 diabetes mellitus. Packer M. Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure. Shah MS, Brownlee M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Rutten FH, Cramer MJ, Lammers JW, Grobbee DE, Hoes AW. Heart failure and chronic obstructive pulmonary disease: an ignored combination? Carter P, Lagan J, Fortune C, Bhatt DL, Vestbo J, Niven R, et al. Association of cardiovascular disease with respiratory disease. Ramalho SHR, Shah AM. Lung function and cardiovascular disease: a link. Trends Cardiov Med. Canepa M, Straburzynska-Migaj E, Drozdz J, Fernandez-Vivancos C, Pinilla JMG, Nyolczas N, et al. Characteristics, treatments and 1-year prognosis of hospitalized and ambulatory heart failure patients with chronic obstructive pulmonary disease in the European society of cardiology heart failure long-term registry. Morgan AD, Rothnie KJ, Bhaskaran K, Smeeth L, Quint JK. Chronic obstructive pulmonary disease and the risk of 12 cardiovascular diseases: a population-based study using UK primary care data. Roversi S, Fabbri LM, Sin DD, Hawkins NM, Agustí A. Chronic obstructive pulmonary disease and cardiac diseases. An urgent need for integrated care. Am J Respir Crit Care Med. Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the GOLD science committee report Eur Respir J. Stone IS, Barnes NC, James WY, Midwinter D, Boubertakh R, Follows R. Lung deflation and cardiovascular structure and function in chronic obstructive pulmonary disease. A randomized controlled trial. Hawkins NM, Virani S, Ceconi C. Heart failure and chronic obstructive pulmonary disease: the challenges facing physicians and health services. Rocha A, Arbex FF, Sperandio PA, Souza A, Biazzim L, Mancuso F, et al. Excess ventilation in chronic obstructive pulmonary disease-heart failure overlap. Implications for dyspnea and exercise intolerance. Horwich TB, Broderick S, Chen L, McCullough PA, Strzelczyk T, Kitzman DW, et al. Relation among body mass index, exercise training, and outcomes in chronic systolic heart failure. Am J Cardiol. Kapoor JR, Heidenreich PA. Obesity and survival in patients with heart failure and preserved systolic function: a U-shaped relationship. Am Heart J. Pandey A, LaMonte M, Klein L, Ayers C, Psaty BM, Eaton CB, et al. Relationship between physical activity, body mass index, and risk of heart failure. Streng KW, Voors AA, Hillege HL, Anker SD, Cleland JG, Dickstein K, et al. Waist-to-hip ratio and mortality in heart failure. Tsujimoto T, Kajio H. Abdominal obesity is associated with an increased risk of all-cause mortality in patients with HFpEF. Obesity-associated heart failure as a theoretical target for treatment with mineralocorticoid receptor antagonists. JAMA Cardiol. Lavie CJ, Ozemek C, Carbone S, Katzmarzyk PT, Blair SN. Sedentary behavior, exercise, and cardiovascular health. Mouton AJ, Li X, Hall ME, Hall JE. Obesity, hypertension, and cardiac dysfunction: novel roles of immunometabolism in macrophage activation and inflammation. Sweeney G. Cardiovascular effects of leptin. Leptin-aldosterone-neprilysin axis: identification of its distinctive role in the pathogenesis of the three phenotypes of heart failure in people with obesity. Mechanick JI, Farkouh ME, Newman JD, Garvey WT. Cardiometabolic-based chronic disease, adiposity and dysglycemia drivers: JACC state-of-the-art review. Abel ED, Litwin SE, Sweeney G. Cardiac remodeling in obesity. Suthahar N, Meijers WC, Ho JE, Gansevoort RT, Voors AA, van der Meer P, et al. Sex-specific associations of obesity and N-terminal pro-B-type natriuretic peptide levels in the general population. Nadruz W Jr, Claggett BL, McMurray JJ, Packer M, Zile MR, et al. Impact of body mass index on the accuracy of n-terminal pro-brain natriuretic peptide and brain natriuretic peptide for predicting outcomes in patients with chronic heart failure and reduced ejection fraction: insights from the PARADIGM-HF study prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial. Kälsch H, Neumann T, Erbel R. Less increase of BNP and NT-proBNP levels in obese patient with decompensated heart failure: interpretation of natriuretic peptides in obesity. Int J Cardiol. Díez J. Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy. de Boer RA, Hulot JS, Tocchetti CG, Aboumsallem JP, Ameri P, Anker SD, et al. Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the translational research committee of the heart failure association HFA of the European society of cardiology ESC. de Boer RA, Meijers WC, van der Meer P, van Veldhuisen DJ. Cancer and heart disease: associations and relations. Anker MS, Sanz AP, Zamorano JL, Mehra MR, Butler J, Riess H, et al. Advanced cancer is also a heart failure syndrome - an hypothesis. Libby P, Sidlow R, Lin AE, Gupta D, Jones LW, Moslehi J, et al. Clonal hematopoiesis: crossroads of aging, cardiovascular disease, and cancer: JACC review topic of the week. Varga ZV, Ferdinandy P, Liaudet L, Pacher P. Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol Heart Circul Physiol. Liu Y, Asnani A, Zou L, Bentley VL, Yu M, Wang Y, et al. Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase. Sci Trans Med. Ogino H, Nakamura K, Iwasa T, Ihara E, Akiho H, Motomura Y, Akahoshi K, Igarashi H, Kato M, Kotoh K, Ito T, Takayanagi R: Regulatory T cells expanded by rapamycin in vitro suppress colitis in an experimental mouse model. J Gastroenterol. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R: mTOR regulates memory CD8 T-cell differentiation. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y: Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG, Pearce EJ: Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS, Lee JY: Hypoxic stress up-regulates the expression of Toll-like receptor 4 in macrophages via hypoxia-inducible factor. Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, Cascante M, Bosca L: Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. Garedew A, Moncada S: Mitochondrial dysfunction and HIF1alpha stabilization in inflammation. J Cell Sci. Hannah S, Mecklenburgh K, Rahman I, Bellingan GJ, Greening A, Haslett C, Chilvers ER: Hypoxia prolongs neutrophil survival in vitro. Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N, Chilvers ER: Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-κB activity. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD: The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. Gergely P, Grossman C, Niland B, Puskas F, Neupane H, Allam F, Banki K, Phillips PE, Perl A: Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus. Pedersen-Lane JH, Zurier RB, Lawrence DA: Analysis of the thiol status of peripheral blood leukocytes in rheumatoid arthritis patients. J Leukoc Biol. Shah D, Wanchu A, Bhatnagar A: Interaction between oxidative stress and chemokines: possible pathogenic role in systemic lupus erythematosus and rheumatoid arthritis. Pedersen BK: Exercise-induced myokines and their role in chronic diseases. Brain Behav Immun. Straub RH, Besedovsky HO: Integrated evolutionary, immunological, and neuroendocrine framework for the pathogenesis of chronic disabling inflammatory diseases. FASEB J. Williams GC: Pleiotropy, natural selection, and the evolution of senescence. Article Google Scholar. Straub RH: [Neuroendocrine immunology: new pathogenetic aspects and clinical application]. Z Rheumatol. Cooper MS, Stewart PM: Corticosteroid insufficiency in acutely ill patients. N Engl J Med. Straub RH: Concepts of evolutionary medicine and energy regulation contribute to the etiology of systemic chronic inflammatory diseases. Buttgereit F, Brand MD, Muller M: ConA induced changes in energy metabolism of rat thymocytes. Biosci Rep. Princiotta MF, Finzi D, Qian SB, Gibbs J, Schuchmann S, Buttgereit F, Bennink JR, Yewdell JW: Quantitating protein synthesis, degradation, and endogenous antigen processing. Maravillas-Montero JL, Santos-Argumedo L: The myosin family: unconventional roles of actin-dependent molecular motors in immune cells. Heasman SJ, Ridley AJ: Multiple roles for RhoA during T cell transendothelial migration. Small Gtpases. Annu Rev Biochem. Procko E, Gaudet R: Antigen processing and presentation: TAPping into ABC transporters. Authier F, Posner BI, Bergeron JJ: Endosomal proteolysis of internalized proteins. White C, Lee J, Kambe T, Fritsche K, Petris MJ: A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity. Marques-da-Silva C, Chaves MM, Rodrigues JC, Corte-Real S, Coutinho-Silva R, Persechini PM: Differential modulation of ATP-induced P2X7-associated permeabilities to cations and anions of macrophages by infection with Leishmania amazonensis. Schenk U, Frascoli M, Proietti M, Geffers R, Traggiai E, Buer J, Ricordi C, Westendorf AM, Grassi F: ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci Signal. Straub RH: Evolutionary medicine and chronic inflammatory state-known and new concepts in pathophysiology. J Mol Med Berl. Download references. Department of Rheumatology and Clinical Immunology, Charité University Medicine Berlin, Charitéplatz 1, , Berlin, Germany. Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, , Regensburg, Germany. You can also search for this author in PubMed Google Scholar. Correspondence to Cornelia M Spies. CMS and FB mainly contributed to the first part of the manuscript cellular energy metabolism , and RHS mainly contributed to the second part of the manuscript energy metabolism in the body and consequence for chronic inflammatory diseases. Reprints and permissions. Spies, C. Energy metabolism and rheumatic diseases: from cell to organism. Arthritis Res Ther 14 , Download citation. Published : 29 June Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Abstract In rheumatic and other chronic inflammatory diseases, high amounts of energy for the activated immune system have to be provided and allocated by energy metabolism. Introduction Energy metabolism is an important part of the background machinery that ensures proper function of immune cells and the immune system [ 1 ]. Energy metabolism in the cell Cellular energy metabolism The main donor of free energy in cells is ATP [ 1 ], which is generated both by glycolysis and by oxidative phosphorylation OXPHOS [ 12 — 14 ]. Figure 1. Full size image. Energy metabolism in the body and consequence for chronic inflammatory diseases Energy metabolism: the systemic function Energy metabolism is not only a question for a single cell or a group of cells such as, for example, T cells or muscle cells, because provision and allocation of energy-rich fuels involves the entire body. Table 2 Energy expenditure of systems and organs under various conditions Full size table. Table 3 The energy appeal reaction Full size table. Conclusions Metabolic pathways drive an energy appeal reaction for the immune response on cellular and organism levels. Abbreviations AMPK: AMP activated protein kinase CID: chronic inflammatory disease FKBP immunophilin FKbinding protein; Glut glucose transporter HIF: hypoxia inducible factor IFN: interferon IL: interleukin mTOR: mammalian target of rapamycin mTORC: mammalian target of rapamycin complex MIF: migration inhibitory factor OXPHOS: oxidative phosphorylation PI3K: phosphoinositide 3-kinase RA: rheumatoid arthritis Th: T-helper type TNF: tumor necrosis factor Treg: regulatory T cell. References Buttgereit F, Burmester GR, Brand MD: Bioenergetics of immune functions: fundamental and therapeutic aspects. Article CAS PubMed Google Scholar Straub RH, Cutolo M, Buttgereit F, Pongratz G: Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. Article CAS PubMed Google Scholar Finlay D, Cantrell DA: Metabolism, migration and memory in cytotoxic T cells. Article PubMed Central CAS PubMed Google Scholar Fox CJ, Hammerman PS, Thompson CB: Fuel feeds function: energy metabolism and the T-cell response. Article CAS PubMed Google Scholar Mathis D, Shoelson SE: Immunometabolism: an emerging frontier. Article CAS PubMed Google Scholar Pearce EL: Metabolism in T cell activation and differentiation. Article PubMed Central CAS PubMed Google Scholar Tannahill GM, O'Neill LA: The emerging role of metabolic regulation in the functioning of Toll-like receptors and the NOD-like receptor Nlrp3. Article CAS PubMed Google Scholar Inoki K, Kim J, Guan KL: AMPK and mTOR in cellular energy homeostasis and drug targets. Article CAS PubMed Google Scholar Nutsch K, Hsieh C: When T cells run out of breath: the HIF-1α story. Article CAS PubMed Google Scholar Powell JD, Pollizzi KN, Heikamp EB, Horton MR: Regulation of immune responses by mTOR. Article PubMed Central PubMed Google Scholar Procaccini C, Galgani M, De Rosa V, Matarese G: Intracellular metabolic pathways control immune tolerance. Article CAS PubMed Google Scholar Gatza E, Wahl DR, Opipari AW, Sundberg TB, Reddy P, Liu C, Glick GD, Ferrara JL: Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease. Article CAS PubMed Google Scholar Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Article PubMed Central CAS PubMed Google Scholar Summers SA, Yin VP, Whiteman EL, Garza LA, Cho H, Tuttle RL, Birnbaum MJ: Signaling pathways mediating insulin-stimulated glucose transport. Article CAS PubMed Google Scholar Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB: The CD28 signaling pathway regulates glucose metabolism. Article CAS PubMed Google Scholar Wofford JA, Wieman HL, Jacobs SR, Zhao Y, Rathmell JC: IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Article PubMed Central CAS PubMed Google Scholar Frauwirth KA, Thompson CB: Regulation of T lymphocyte metabolism. Article CAS PubMed Google Scholar Hay N, Sonenberg N: Upstream and downstream of mTOR. Article CAS PubMed Google Scholar Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD: Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Article CAS PubMed Google Scholar Hardie DG: AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Article PubMed Central CAS PubMed Google Scholar Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ: AMPK phosphorylation of raptor mediates a metabolic checkpoint. Article PubMed Central CAS PubMed Google Scholar Huang W, Ramsey KM, Marcheva B, Bass J: Circadian rhythms, sleep, and metabolism. Article PubMed Central CAS PubMed Google Scholar Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, Vasquez DS, Juguilon H, Panda S, Shaw RJ, Thompson CB, Evans RM: AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Article CAS PubMed Google Scholar Gaber T, Dziurla R, Tripmacher R, Burmester GR, Buttgereit F: Hypoxia inducible factor HIF in rheumatology: low O 2! Article CAS PubMed Google Scholar Falchuk KH, Goetzl EJ, Kulka JP: Respiratory gases of synovial fluids. Article CAS PubMed Google Scholar Lund-Olesen K: Oxygen tension in synovial fluids. Article CAS PubMed Google Scholar Sivakumar B, Akhavani MA, Winlove CP, Taylor PC, Paleolog EM, Kang N: Synovial hypoxia as a cause of tendon rupture in rheumatoid arthritis. Article PubMed Google Scholar Ng CT, Biniecka M, Kennedy A, McCormick J, Fitzgerald O, Bresnihan B, Buggy D, Taylor CT, O'Sullivan J, Fearon U, Veale DJ: Synovial tissue hypoxia and inflammation in vivo. Article PubMed Central CAS PubMed Google Scholar Kennedy A, Ng CT, Chang TC, Biniecka M, O'Sullivan JN, Heffernan E, Fearon U, Veale DJ: Tumor necrosis factor blocking therapy alters joint inflammation and hypoxia. Article CAS PubMed Google Scholar Wang GL, Semenza GL: Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. Article CAS PubMed Google Scholar Nakamura H, Makino Y, Okamoto K, Poellinger L, Ohnuma K, Morimoto C, Tanaka H: TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells. Article CAS PubMed Google Scholar Hollander AP, Corke KP, Freemont AJ, Lewis CE: Expression of hypoxia-inducible factor 1α by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint. Article CAS PubMed Google Scholar Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS: HIF-1alpha is essential for myeloid cell-mediated inflammation. Article PubMed Central CAS PubMed Google Scholar van Hal TW, van Bon L, Radstake TR: A system out of breath: how hypoxia possibly contributes to the pathogenesis of systemic sclerosis. Article PubMed Central PubMed Google Scholar Distler O, Distler JH, Scheid A, Acker T, Hirth A, Rethage J, Michel BA, Gay RE, Muller-Ladner U, Matucci-Cerinic M, Plate KH, Gassmann M, Gay S: Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Article CAS PubMed Google Scholar Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD: The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Article PubMed Central CAS PubMed Google Scholar Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H: HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. Article PubMed Central CAS PubMed Google Scholar Moran EM, Heydrich R, Ng CT, Saber TP, McCormick J, Sieper J, Appel H, Fearon U, Veale DJ: ILA expression is localised to both mononuclear and polymorphonuclear synovial cell infiltrates. Article PubMed Central CAS PubMed Google Scholar Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A: Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Article CAS PubMed Google Scholar Chang X, Wei C: Glycolysis and rheumatoid arthritis. Article PubMed Google Scholar Henderson B, Bitensky L, Chayen J: Glycolytic activity in human synovial lining cells in rheumatoid arthritis. Article PubMed Central CAS PubMed Google Scholar Matsumoto I, Lee DM, Goldbach-Mansky R, Sumida T, Hitchon CA, Schur PH, Anderson RJ, Coblyn JS, Weinblatt ME, Brenner M, Duclos B, Pasquali JL, El-Gabalawy H, Mathis D, Benoist C: Low prevalence of antibodies to glucosephosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders. Article CAS PubMed Google Scholar Matsumoto I, Staub A, Benoist C, Mathis D: Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Article CAS PubMed Google Scholar Fernandez D, Bonilla E, Mirza N, Niland B, Perl A: Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Article PubMed Central CAS PubMed Google Scholar Warner LM, Adams LM, Sehgal SN: Rapamycin prolongs survival and arrests pathophysiologic changes in murine systemic lupus erythematosus. Article CAS PubMed Google Scholar Fernandez D, Perl A: mTOR signaling: a central pathway to pathogenesis in systemic lupus erythematosus?. PubMed Central PubMed Google Scholar Yoshizaki A, Yanaba K, Iwata Y, Komura K, Ogawa F, Takenaka M, Shimizu K, Asano Y, Hasegawa M, Fujimoto M, Sato S: Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Article CAS PubMed Google Scholar Su TI, Khanna D, Furst DE, Danovitch G, Burger C, Maranian P, Clements PJ: Rapamycin versus methotrexate in early diffuse systemic sclerosis: results from a randomized, single-blind pilot study. Article CAS PubMed Google Scholar Ogino H, Nakamura K, Iwasa T, Ihara E, Akiho H, Motomura Y, Akahoshi K, Igarashi H, Kato M, Kotoh K, Ito T, Takayanagi R: Regulatory T cells expanded by rapamycin in vitro suppress colitis in an experimental mouse model. Article PubMed Google Scholar Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R: mTOR regulates memory CD8 T-cell differentiation. Article PubMed Central CAS PubMed Google Scholar Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y: Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Article PubMed Central CAS PubMed Google Scholar Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG, Pearce EJ: Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Article PubMed Central CAS PubMed Google Scholar Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS, Lee JY: Hypoxic stress up-regulates the expression of Toll-like receptor 4 in macrophages via hypoxia-inducible factor. Article PubMed Central CAS PubMed Google Scholar Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, Cascante M, Bosca L: Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. Article CAS PubMed Google Scholar Garedew A, Moncada S: Mitochondrial dysfunction and HIF1alpha stabilization in inflammation. Article CAS PubMed Google Scholar Hannah S, Mecklenburgh K, Rahman I, Bellingan GJ, Greening A, Haslett C, Chilvers ER: Hypoxia prolongs neutrophil survival in vitro. Article CAS PubMed Google Scholar Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N, Chilvers ER: Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-κB activity. Article PubMed Central CAS PubMed Google Scholar Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD: The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Some of the most widely studied mechanisms include inflammation, oxidative stress, insulin resistance, and mitochondrial dysfunction. With regards to the latter, obesity not only precipitates mitochondrial dysfunction, but causes several perturbations in how the body metabolizes fuel i. carbohydrates, fatty acids. Understanding the molecular dysregulation that causes these metabolic perturbations in obesity may represent an untapped pool of metabolic targets for pharmacotherapy. This Special Issue aims to welcome studies focused on expanding our knowledge of intermediary energy metabolism perturbations in the pathology of obesity related chronic diseases, with an emphasis on T2D and CVD. Furthermore, this issue will publish studies illustrating the potential of correcting these perturbations in intermediary energy metabolism with pharmacotherapy, and the potential safety concerns involved. A comprehensive coverage of all aspects of this expanding field will broaden the scientific community in its pursuit of developing new strategies to tackle the obesity epidemic. This Special Issue welcomes a wide range of diversity in input by seeking Original Research, Reviews, Mini Reviews, Case Reports, and Brief Research report articles, all of which will undergo full peer review. For authors, please also review the journal's information regarding Author Guidelines and Article Processing Charges , or direct any questions to the Editorial Office. |
| Metabolic syndrome | J Virol. However, the role of chhronic Energy metabolism and chronic diseases HF chronuc long been controversial. Hypoxia might Energy metabolism and chronic diseases play a central role in pathogenesis of systemic sclerosis by augmenting vascular disease and tissue fibrosis [ 4041 ]. Immune and non-immune functions of adipose tissue leukocytes. Activation of quiescent leukocytes leads to an increase of energy expenditure by a factor of 1. Mayo Clinic Q and A: Metabolic syndrome and lifestyle changes. |
| Pharmacotherapy of Energy Metabolism in Obesity | Frontiers Publishing Partnerships Special Issue | Comorbidity of atrial fibrillation and heart failure. Innate immune cells, such as neutrophils, natural killer cells, and mast cells 52 , have been revealed to participate in the progress of HF through immune inflammation. An overview of normal physiological metabolic processes and the pathological metabolic remodeling characteristic of HF. Individuals with COVID also feature increased levels of ketone bodies in serum and urine Exp Physiol. This article is part of the Research Topic The Relationship Between Cardiovascular Disease and Other Chronic Conditions View all 39 Articles. COVID and diabetes: A collision and collusion of two diseases. |
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Something REALLY CRAZY COULD HAPPEN with Baltimore Ravens! Obesity Energyy a major risk factor for metanolism type metabolksm Pre-workout meal ideas T2D and cardiovascular disease CVD. Peppermint oil for skin, Examining nutrition myths metaabolism has been placed on understanding mechanisms dkseases contribute to Energy metabolism and chronic diseases obesity predisposes to the pathology of T2D and CVD. Some of the most widely studied mechanisms include inflammation, oxidative stress, insulin resistance, and mitochondrial dysfunction. With regards to the latter, obesity not only precipitates mitochondrial dysfunction, but causes several perturbations in how the body metabolizes fuel i. carbohydrates, fatty acids. Understanding the molecular dysregulation that causes these metabolic perturbations in obesity may represent an untapped pool of metabolic targets for pharmacotherapy.Energy metabolism and chronic diseases -
J Gastroenterol. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R: mTOR regulates memory CD8 T-cell differentiation. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y: Enhancing CD8 T-cell memory by modulating fatty acid metabolism.
Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG, Pearce EJ: Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation.
Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS, Lee JY: Hypoxic stress up-regulates the expression of Toll-like receptor 4 in macrophages via hypoxia-inducible factor. Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, Cascante M, Bosca L: Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation.
Garedew A, Moncada S: Mitochondrial dysfunction and HIF1alpha stabilization in inflammation. J Cell Sci. Hannah S, Mecklenburgh K, Rahman I, Bellingan GJ, Greening A, Haslett C, Chilvers ER: Hypoxia prolongs neutrophil survival in vitro.
Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N, Chilvers ER: Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-κB activity. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD: The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.
Nat Med. Gergely P, Grossman C, Niland B, Puskas F, Neupane H, Allam F, Banki K, Phillips PE, Perl A: Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus.
Pedersen-Lane JH, Zurier RB, Lawrence DA: Analysis of the thiol status of peripheral blood leukocytes in rheumatoid arthritis patients. J Leukoc Biol.
Shah D, Wanchu A, Bhatnagar A: Interaction between oxidative stress and chemokines: possible pathogenic role in systemic lupus erythematosus and rheumatoid arthritis. Pedersen BK: Exercise-induced myokines and their role in chronic diseases. Brain Behav Immun. Straub RH, Besedovsky HO: Integrated evolutionary, immunological, and neuroendocrine framework for the pathogenesis of chronic disabling inflammatory diseases.
FASEB J. Williams GC: Pleiotropy, natural selection, and the evolution of senescence. Article Google Scholar. Straub RH: [Neuroendocrine immunology: new pathogenetic aspects and clinical application]. Z Rheumatol. Cooper MS, Stewart PM: Corticosteroid insufficiency in acutely ill patients.
N Engl J Med. Straub RH: Concepts of evolutionary medicine and energy regulation contribute to the etiology of systemic chronic inflammatory diseases. Buttgereit F, Brand MD, Muller M: ConA induced changes in energy metabolism of rat thymocytes.
Biosci Rep. Princiotta MF, Finzi D, Qian SB, Gibbs J, Schuchmann S, Buttgereit F, Bennink JR, Yewdell JW: Quantitating protein synthesis, degradation, and endogenous antigen processing.
Maravillas-Montero JL, Santos-Argumedo L: The myosin family: unconventional roles of actin-dependent molecular motors in immune cells. Heasman SJ, Ridley AJ: Multiple roles for RhoA during T cell transendothelial migration.
Small Gtpases. Annu Rev Biochem. Procko E, Gaudet R: Antigen processing and presentation: TAPping into ABC transporters.
Authier F, Posner BI, Bergeron JJ: Endosomal proteolysis of internalized proteins. White C, Lee J, Kambe T, Fritsche K, Petris MJ: A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity.
Marques-da-Silva C, Chaves MM, Rodrigues JC, Corte-Real S, Coutinho-Silva R, Persechini PM: Differential modulation of ATP-induced P2X7-associated permeabilities to cations and anions of macrophages by infection with Leishmania amazonensis.
Schenk U, Frascoli M, Proietti M, Geffers R, Traggiai E, Buer J, Ricordi C, Westendorf AM, Grassi F: ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci Signal. Straub RH: Evolutionary medicine and chronic inflammatory state-known and new concepts in pathophysiology.
J Mol Med Berl. Download references. Department of Rheumatology and Clinical Immunology, Charité University Medicine Berlin, Charitéplatz 1, , Berlin, Germany.
Laboratory of Experimental Rheumatology and Neuroendocrino-Immunology, Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, , Regensburg, Germany. You can also search for this author in PubMed Google Scholar. Correspondence to Cornelia M Spies.
CMS and FB mainly contributed to the first part of the manuscript cellular energy metabolism , and RHS mainly contributed to the second part of the manuscript energy metabolism in the body and consequence for chronic inflammatory diseases.
Reprints and permissions. Spies, C. Energy metabolism and rheumatic diseases: from cell to organism. Arthritis Res Ther 14 , Download citation.
Published : 29 June Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.
Skip to main content. Search all BMC articles Search. Download PDF. Abstract In rheumatic and other chronic inflammatory diseases, high amounts of energy for the activated immune system have to be provided and allocated by energy metabolism. Introduction Energy metabolism is an important part of the background machinery that ensures proper function of immune cells and the immune system [ 1 ].
Energy metabolism in the cell Cellular energy metabolism The main donor of free energy in cells is ATP [ 1 ], which is generated both by glycolysis and by oxidative phosphorylation OXPHOS [ 12 — 14 ].
Figure 1. Full size image. Energy metabolism in the body and consequence for chronic inflammatory diseases Energy metabolism: the systemic function Energy metabolism is not only a question for a single cell or a group of cells such as, for example, T cells or muscle cells, because provision and allocation of energy-rich fuels involves the entire body.
Table 2 Energy expenditure of systems and organs under various conditions Full size table. Table 3 The energy appeal reaction Full size table. Conclusions Metabolic pathways drive an energy appeal reaction for the immune response on cellular and organism levels.
Abbreviations AMPK: AMP activated protein kinase CID: chronic inflammatory disease FKBP immunophilin FKbinding protein; Glut glucose transporter HIF: hypoxia inducible factor IFN: interferon IL: interleukin mTOR: mammalian target of rapamycin mTORC: mammalian target of rapamycin complex MIF: migration inhibitory factor OXPHOS: oxidative phosphorylation PI3K: phosphoinositide 3-kinase RA: rheumatoid arthritis Th: T-helper type TNF: tumor necrosis factor Treg: regulatory T cell.
References Buttgereit F, Burmester GR, Brand MD: Bioenergetics of immune functions: fundamental and therapeutic aspects. Article CAS PubMed Google Scholar Straub RH, Cutolo M, Buttgereit F, Pongratz G: Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases.
Article CAS PubMed Google Scholar Finlay D, Cantrell DA: Metabolism, migration and memory in cytotoxic T cells. Article PubMed Central CAS PubMed Google Scholar Fox CJ, Hammerman PS, Thompson CB: Fuel feeds function: energy metabolism and the T-cell response. Article CAS PubMed Google Scholar Mathis D, Shoelson SE: Immunometabolism: an emerging frontier.
Article CAS PubMed Google Scholar Pearce EL: Metabolism in T cell activation and differentiation. Article PubMed Central CAS PubMed Google Scholar Tannahill GM, O'Neill LA: The emerging role of metabolic regulation in the functioning of Toll-like receptors and the NOD-like receptor Nlrp3.
Article CAS PubMed Google Scholar Inoki K, Kim J, Guan KL: AMPK and mTOR in cellular energy homeostasis and drug targets. Article CAS PubMed Google Scholar Nutsch K, Hsieh C: When T cells run out of breath: the HIF-1α story. Article CAS PubMed Google Scholar Powell JD, Pollizzi KN, Heikamp EB, Horton MR: Regulation of immune responses by mTOR.
Article PubMed Central PubMed Google Scholar Procaccini C, Galgani M, De Rosa V, Matarese G: Intracellular metabolic pathways control immune tolerance.
Article CAS PubMed Google Scholar Gatza E, Wahl DR, Opipari AW, Sundberg TB, Reddy P, Liu C, Glick GD, Ferrara JL: Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease.
Article CAS PubMed Google Scholar Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation.
Article PubMed Central CAS PubMed Google Scholar Summers SA, Yin VP, Whiteman EL, Garza LA, Cho H, Tuttle RL, Birnbaum MJ: Signaling pathways mediating insulin-stimulated glucose transport. Article CAS PubMed Google Scholar Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB: The CD28 signaling pathway regulates glucose metabolism.
Article CAS PubMed Google Scholar Wofford JA, Wieman HL, Jacobs SR, Zhao Y, Rathmell JC: IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Article PubMed Central CAS PubMed Google Scholar Frauwirth KA, Thompson CB: Regulation of T lymphocyte metabolism.
Article CAS PubMed Google Scholar Hay N, Sonenberg N: Upstream and downstream of mTOR. Article CAS PubMed Google Scholar Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD: Activation of a metabolic gene regulatory network downstream of mTOR complex 1.
Article CAS PubMed Google Scholar Hardie DG: AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function.
Article PubMed Central CAS PubMed Google Scholar Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ: AMPK phosphorylation of raptor mediates a metabolic checkpoint.
Article PubMed Central CAS PubMed Google Scholar Huang W, Ramsey KM, Marcheva B, Bass J: Circadian rhythms, sleep, and metabolism. Article PubMed Central CAS PubMed Google Scholar Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, Vasquez DS, Juguilon H, Panda S, Shaw RJ, Thompson CB, Evans RM: AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation.
Article CAS PubMed Google Scholar Gaber T, Dziurla R, Tripmacher R, Burmester GR, Buttgereit F: Hypoxia inducible factor HIF in rheumatology: low O 2! Article CAS PubMed Google Scholar Falchuk KH, Goetzl EJ, Kulka JP: Respiratory gases of synovial fluids.
Article CAS PubMed Google Scholar Lund-Olesen K: Oxygen tension in synovial fluids. Article CAS PubMed Google Scholar Sivakumar B, Akhavani MA, Winlove CP, Taylor PC, Paleolog EM, Kang N: Synovial hypoxia as a cause of tendon rupture in rheumatoid arthritis.
Article PubMed Google Scholar Ng CT, Biniecka M, Kennedy A, McCormick J, Fitzgerald O, Bresnihan B, Buggy D, Taylor CT, O'Sullivan J, Fearon U, Veale DJ: Synovial tissue hypoxia and inflammation in vivo.
Article PubMed Central CAS PubMed Google Scholar Kennedy A, Ng CT, Chang TC, Biniecka M, O'Sullivan JN, Heffernan E, Fearon U, Veale DJ: Tumor necrosis factor blocking therapy alters joint inflammation and hypoxia. Article CAS PubMed Google Scholar Wang GL, Semenza GL: Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia.
Article CAS PubMed Google Scholar Nakamura H, Makino Y, Okamoto K, Poellinger L, Ohnuma K, Morimoto C, Tanaka H: TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells.
Article CAS PubMed Google Scholar Hollander AP, Corke KP, Freemont AJ, Lewis CE: Expression of hypoxia-inducible factor 1α by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint.
Article CAS PubMed Google Scholar Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS: HIF-1alpha is essential for myeloid cell-mediated inflammation.
Article PubMed Central CAS PubMed Google Scholar van Hal TW, van Bon L, Radstake TR: A system out of breath: how hypoxia possibly contributes to the pathogenesis of systemic sclerosis. Article PubMed Central PubMed Google Scholar Distler O, Distler JH, Scheid A, Acker T, Hirth A, Rethage J, Michel BA, Gay RE, Muller-Ladner U, Matucci-Cerinic M, Plate KH, Gassmann M, Gay S: Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis.
Article CAS PubMed Google Scholar Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD: The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Article PubMed Central CAS PubMed Google Scholar Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H: HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.
Article PubMed Central CAS PubMed Google Scholar Moran EM, Heydrich R, Ng CT, Saber TP, McCormick J, Sieper J, Appel H, Fearon U, Veale DJ: ILA expression is localised to both mononuclear and polymorphonuclear synovial cell infiltrates.
Article PubMed Central CAS PubMed Google Scholar Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A: Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia.
Article CAS PubMed Google Scholar Chang X, Wei C: Glycolysis and rheumatoid arthritis. Article PubMed Google Scholar Henderson B, Bitensky L, Chayen J: Glycolytic activity in human synovial lining cells in rheumatoid arthritis.
Article PubMed Central CAS PubMed Google Scholar Matsumoto I, Lee DM, Goldbach-Mansky R, Sumida T, Hitchon CA, Schur PH, Anderson RJ, Coblyn JS, Weinblatt ME, Brenner M, Duclos B, Pasquali JL, El-Gabalawy H, Mathis D, Benoist C: Low prevalence of antibodies to glucosephosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders.
Article CAS PubMed Google Scholar Matsumoto I, Staub A, Benoist C, Mathis D: Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme.
Article CAS PubMed Google Scholar Fernandez D, Bonilla E, Mirza N, Niland B, Perl A: Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus.
Article PubMed Central CAS PubMed Google Scholar Warner LM, Adams LM, Sehgal SN: Rapamycin prolongs survival and arrests pathophysiologic changes in murine systemic lupus erythematosus. Article CAS PubMed Google Scholar Fernandez D, Perl A: mTOR signaling: a central pathway to pathogenesis in systemic lupus erythematosus?.
PubMed Central PubMed Google Scholar Yoshizaki A, Yanaba K, Iwata Y, Komura K, Ogawa F, Takenaka M, Shimizu K, Asano Y, Hasegawa M, Fujimoto M, Sato S: Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Article CAS PubMed Google Scholar Su TI, Khanna D, Furst DE, Danovitch G, Burger C, Maranian P, Clements PJ: Rapamycin versus methotrexate in early diffuse systemic sclerosis: results from a randomized, single-blind pilot study.
Article CAS PubMed Google Scholar Ogino H, Nakamura K, Iwasa T, Ihara E, Akiho H, Motomura Y, Akahoshi K, Igarashi H, Kato M, Kotoh K, Ito T, Takayanagi R: Regulatory T cells expanded by rapamycin in vitro suppress colitis in an experimental mouse model.
Article PubMed Google Scholar Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R: mTOR regulates memory CD8 T-cell differentiation. Article PubMed Central CAS PubMed Google Scholar Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y: Enhancing CD8 T-cell memory by modulating fatty acid metabolism.
Article PubMed Central CAS PubMed Google Scholar Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG, Pearce EJ: Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation.
Article PubMed Central CAS PubMed Google Scholar Kim SY, Choi YJ, Joung SM, Lee BH, Jung YS, Lee JY: Hypoxic stress up-regulates the expression of Toll-like receptor 4 in macrophages via hypoxia-inducible factor. Article PubMed Central CAS PubMed Google Scholar Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, Cascante M, Bosca L: Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation.
Article CAS PubMed Google Scholar Garedew A, Moncada S: Mitochondrial dysfunction and HIF1alpha stabilization in inflammation.
Article CAS PubMed Google Scholar Hannah S, Mecklenburgh K, Rahman I, Bellingan GJ, Greening A, Haslett C, Chilvers ER: Hypoxia prolongs neutrophil survival in vitro.
Article CAS PubMed Google Scholar Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N, Chilvers ER: Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-κB activity.
Article PubMed Central CAS PubMed Google Scholar Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD: The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Article PubMed Central CAS PubMed Google Scholar Gergely P, Grossman C, Niland B, Puskas F, Neupane H, Allam F, Banki K, Phillips PE, Perl A: Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus.
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Metabolism is the process your body uses to get or make energy from the food you eat. Food is made up of proteins, carbohydrates, and fats. Chemicals in your digestive system break the food parts down into sugars and acids, your body's fuel. Your body can use this fuel right away, or it can store the energy in your body tissues, such as your liver, muscles, and body fat.
A metabolic disorder occurs when abnormal chemical reactions in your body disrupt this process. When this happens, you might have too much of some substances or too little of other ones that you need to stay healthy.
There are different groups of disorders. Some affect the breakdown of amino acids , carbohydrates , or lipids. Another group, mitochondrial diseases , affects the parts of the cells that produce the energy.
A comprehensive coverage of all aspects of this expanding field will broaden the scientific community in its pursuit of developing new strategies to tackle the obesity epidemic. This Special Issue welcomes a wide range of diversity in input by seeking Original Research, Reviews, Mini Reviews, Case Reports, and Brief Research report articles, all of which will undergo full peer review.
For authors, please also review the journal's information regarding Author Guidelines and Article Processing Charges , or direct any questions to the Editorial Office.
Abstract Deadline: 3 July Manuscript deadline: 1 December Keywords : obesity, type 2 diabetes, cardiovascular disease, energy metabolism, pharmacotherapy. Manuscripts can be submitted to this Special Issue via the following journals:. total views article views article downloads topic views.
Special Issue Pharmacotherapy of Energy Metabolism in Obesity. Submit your abstract Submit your manuscript Participate.
Much metaboolism modern Western medicine is based Enfrgy the treatment of Enrrgy, Examining nutrition myths harm, from physical injury Disewses infections, from broken bones and the common cold to heart and asthma attacks. But progress in treating chronic illness, Waist circumference and weight management the Energy metabolism and chronic diseases of the problem is ahd unknown -- and, in Energy metabolism and chronic diseases, may no longer even be present Citrus aurantium for mental alertness has lagged. Chronic conditions like cancer, diabetes and cardiovascular disease defy easy explanation, let alone remedy. The Centers for Disease Control and Prevention cyronic that more than half of adults and one-third of children and teens in the United States live with at least one chronic illness. Chronic medical conditions, according to the National Institutes of Health, cause more than half of all deaths worldwide. In a new paper, available cbronic in Mitochondrion in advance of publication, Robert K. Naviaux, MD, PhD, professor of medicine, pediatrics and pathology at University of California San Diego School of Medicine, posits that chronic disease is essentially the consequence of the natural healing cycle becoming blocked, specifically by disruptions at the metabolic and cellular levels.
Die Kleinigkeiten!
ich weiß nicht, ich weiß nicht
Nach meiner Meinung lassen Sie den Fehler zu. Es ich kann beweisen. Schreiben Sie mir in PM, wir werden reden.
Ich denke es schon wurde besprochen.
der Maßgebliche Standpunkt, es ist lustig...