Insulin resistance and inflammation -
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In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Chronic inflammation occurs in obese conditions in both humans and animals. It also contributes to the pathogenesis of type 2 diabetes T2D through insulin resistance, a status in which the body loses its ability to respond to insulin.
Inflammation impairs insulin signaling through the functional inhibition of IRS-1 and PPARγ. Insulin sensitizers such as rosiglitazone and pioglitazone inhibit inflammation while improving insulin sensitivity. Therefore, anti-inflammatory agents have been suggested as a treatment strategy for insulin resistance.
This strategy has been tested in laboratory studies and clinical trials for more than 10 years; however, no significant progress has been made in any of the model systems. This status has led us to re-evaluate the biological significance of chronic inflammation in obesity.
Recent studies have consistently asserted that obesity-associated inflammation helps to maintain insulin sensitivity. Inflammation stimulates local adipose tissue remodeling and promotes systemic energy expenditure.
We propose that these beneficial activities of inflammation provide an underlying mechanism for the failure of anti-inflammatory therapy in the treatment of insulin resistance. Current literature will be reviewed in this article to present evidence that supports this viewpoint.
Wei Ying, Wenxian Fu, … Jerrold M. Mengwei Li, Xiaowei Chi, … Hanmei Xu. Noha F. Hassan, Azza H. For about two decades, it has been known that inflammation contributes to obesity-associated insulin resistance.
Inflammatory cytokines eg , TNF-alpha, IL-1, and IL-6 have been shown to induce insulin resistance in multiple organs fat, muscle and liver. TNF-α elevation was found in adipose tissue of obese mice in 1. That study provided the first evidence of the role of chronic inflammation during obesity and its association with insulin resistance in an animal model.
Macrophages in adipose tissue are the major source of inflammatory cytokines in obesity 2 , 3. Recent studies from multiple groups, including ours, consistently suggest that adipose tissue hypoxia is a root of chronic inflammation in obesity 4.
Hypoxia is likely the result of a reduction in blood flow to adipose tissue, which is supported by some studies in humans and animals 5 , 6 , 7. In addition to adipose tissue hypoxia, metabolites of fatty acids and glucose, including diacylglyceride DAG , ceramide, and reactive oxygen species, also contribute to the chronic inflammation in obesity.
They activate the inflammatory response in several ways. They can directly interact with signaling kinases PKCs, JNKs, and IKKs in cells 8 ; the lipids can also signal through cell membrane receptors for lipids, such as TLR4, CD36, or GPR 8 , 9 , 10 , 11 , 12 , Fat or glucose oxygenation in the mitochondria can also generate reactive oxygen species ROS , which can then induce activation of the inflammatory kinases JNK and IKK in the cytoplasm.
The lipids also induce endoplasmic reticulum ER stress to activate JNK and IKK 14 , In obesity, these signaling pathways are activated as a result of the surplus calories and involved in the pathogenesis of chronic inflammation.
In cellular models of insulin resistance, the pro-inflammatory cytokine, TNF-α, is widely used to induce insulin resistance. The data from these cellular studies suggest that TNF-α is a major risk factor for insulin resistance in obesity and other chronic diseases 1 , 16 , TNF-α inhibits insulin signaling by serine phosphorylation of IRS-1, which leads to the dissociation of IRS-1 from the insulin receptor and causes degradation of IRS-1 protein 17 , 18 , TNF-α induces insulin resistance by IRS-1 serine phosphorylation through the activation of several serine kinases, including JNK 20 , 21 , IKK 22 , ERK 23 , 24 , 25 , PKC 26 , 27 , 28 , Akt 28 , 29 , GSK-3 30 , 31 , 32 , IRAK 33 , and mTOR 34 , Serine phosphorylation induces IRS-1 degradation and serves as a negative feedback signal to impair insulin action The pathway has been under active investigation in the obesity field after IKKβ was found to induce insulin resistance in obese mice The serine kinase IKK has three major isoforms, including IKKα IKK1 , IKKβ IKK2 , and IKKγ, which requires IKKβ for NF-κB activation In obesity, IKKβ is activated by several intracellular signals, such as ROS, ER stress, DAG, and ceramide.
IKKβ is also activated by extracellular stimuli, including TNF-α, IL-1, fatty acids 11 and hypoxia IKKβ induces NF-κB activation by phosphorylation of the Inhibitor of Kappa B alpha IκBα NF-κB is a ubiquitous transcription factor that is formed by two subunits of the Rel family, which includes seven members, p65 RelA , p50 NF-κB1 , c-Rel, RelB, p, p, p52 These members form a homodimer or heterodimer that regulates gene transcription.
In most cases, NF-κB is a heterodimer of p65 and p P65 contains the transactivation domain and mediates the transcriptional activity of NF-κB. P50 inhibits the transcriptional activity of p65 42 , and the NF-κB activity is enhanced in p50 knockout mice NF-κB inhibits PPARγ function through the competition for transcriptional coactivators or the exchange of corepressors with PPARγ This process is responsible for inhibiting PPAR-target genes, such as CAP and IRS Our study shows that IKK promotes the activity of HDAC3 in the nuclear corepressor complex.
IKK induces nuclear translocation of HDAC3 from the cytoplasm. In the cytosol, HDAC3 associates with IκBα, and the degradation of IκBα promotes HDAC3 translocation into the nucleus. The PPARγ inactivation leads to suppression of IRS-2 expression, a signaling molecule in insulin signaling pathways for Glut4 translocation.
Elevated plasma free fatty acids FFAs induce insulin resistance in obese and diabetic subjects It was known as early as that lipid infusion caused insulin resistance 46 , PKCθ is a major kinase involved in FFA-induced insulin resistance According to the Randle glucose-fatty acid cycle, the preferential oxidation of free fatty acids over glucose plays a major role in the pathogenesis of insulin sensitivity Local accumulation of fat metabolites, such as ceramides, diacylglycerol or acyl-CoA, inside skeletal muscle and liver may activate a serine kinase cascade, leading to defects in insulin signaling and glucose transport Inflammation is associated with increased energy expenditure in patients with chronic kidney disease 51 , cachexia 52 , inflammatory bowel disease 53 and Crohn's disease NF-κB activity can promote energy expenditure, as supported by documents on energy expenditure in cachexia 55 , 56 and infection.
However, the role of NF-κB in energy expenditure was not tested in transgenic models. To this end, we have investigated energy metabolism in transgenic mice with elevated NF-κB activity. The transcriptional activity of NF-κB is enhanced either by over-expression of NF-κB p65 in the fat tissue, or inactivation of NF-κB p50 by global gene knockout 57 , In these two models, inflammatory cytokines TNF-α and IL-6 were elevated in the blood, and energy expenditure was increased both during the day and at night 57 , Expression of TNF-α and IL-1 mRNA was increased in adipose tissue and macrophages.
These cytokines are positively associated with energy expenditure in the body In transgenic mice with deficiencies in these cytokines or their receptors, energy accumulation is enhanced and energy expenditure is reduced.
This positive energy balance has been reported in transgenic mice deficient in TNF-α 59 , IL-1 60 , or IL-6 The above literature suggests that energy accumulation induces chronic inflammation. Inflammation may promote energy expenditure in a feedback manner to counteract an energy surplus In the peripheral tissues, inflammation induces fat mobilization and oxidation to promote energy expenditure.
In the central nervous system, inflammation can inhibit food intake and activate neurons for energy expenditure, while inhibition of inflammation leads to fat accumulation These changes were associated with reduced hepatic glucose production and improvements in insulin-stimulated glucose disposal, assessed during hyperinsulinemic-euglycemic clamping 63 , 64 , 65 , Aspirin inhibits the activity of multiple kinases induced by TNF-α, such as JNK, IKK, Akt, and mTOR.
It may enhance insulin sensitivity by protecting the IRS proteins from serine phosphorylation However, the therapeutic value of high-dose aspirin is limited by its side effects, including gastrointestinal irritation and high risk of bleeding.
Statins, a class of anti-inflammatory drugs, have been shown to downregulate the transcriptional activity of NF-κB, AP-1, and HIF-1α 65 , 69 , with coordinated reductions in the expression of prothrombotic and inflammatory cytokines.
Randomized clinical trials have demonstrated that statins reduces CRP, multiple cytokines, and inflammatory markers in the body. Even with modest anti-inflammatory properties, statins do not appear to enhance insulin resistance or significantly improve glycemia A recent review published in JAMA suggests that statin therapy is associated with excess risk for diabetes mellitus.
The researchers analyzed five earlier trials, involving 32 patients, to test the effect of the drug dose. Those getting intensive treatment were 12 percent more likely to have diabetes 71 , which translates into a 20 percent increase in developing diabetes in the high-dose statin users compared to those who do not take the drugs.
Glucocorticoids are the most effective anti-inflammatory drugs used to treat inflammatory diseases. Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. In a clinical study, the effect of dexamethasone on insulin-stimulated glucose disposal was investigated with a double-blind, placebo-controlled, cross-over trial comparing insulin sensitivity measured by the euglycemic hyperinsulinemic clamp in young healthy males allocated the placebo or 1 mg dexamethasone twice daily for 6 d, each in random order.
This indicates that strong inhibition of inflammation may block the beneficial effects of inflammation on insulin sensitivity. Interleukin-1β induces inflammation in islets of patients with type 2 diabetes The interleukin-1—receptor antagonist, a naturally occurring competitive inhibitor of interleukin-1 75 , protects human beta cells from glucose-induced functional impairment and apoptosis The expression of the interleukinreceptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus.
High glucose induces the production of interleukin-1β in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and enhanced apoptosis.
In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes 74 , 34 patients were randomly assigned to receive mg of anakinra a recombinant human interleukinreceptor antagonist subcutaneously once daily for 13 weeks.
In the control group, 36 patients received placebo. All patients underwent an oral glucose-tolerance test. At the end of the study, the two study groups exhibited no difference in insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index.
However, the therapy did improve blood glucose levels. The authors conclude that the improvement is from enhanced pancreatic β-cell function.
This study indicates that inhibition of IL-1β improves glucose metabolism, independent of insulin sensitivity. TNF-α expression is elevated in the adipose tissue of obese rodents and humans.
In animal studies, administration of exogenous TNF-α induced insulin resistance, whereas neutralization of TNF-α improved insulin sensitivity. TNF-α knockout mice were used to examine the role of TNF-α in obesity-associated insulin resistance The KO mice were compared with WT mice in lean and obese induced by gold-thioglucose [GTG]-injection conditions at 13, 19, and 28 weeks of age.
In the obese condition, the body weight was identical between the KO and WT mice. Glucose levels were significantly increased in both groups during the OGTT. This indicates that the absence of TNF-α is not sufficient to protect mice from insulin resistance in obese conditions Some animal studies 78 and several clinical trials using TNF antagonism have thus far failed to improve insulin sensitivity 79 , 80 , 81 , 82 , These facts suggest that there are many unknowns in the relationship of obesity-associated inflammation and insulin resistance.
The role of IL-6 in the pathogenesis of obesity and insulin resistance is controversial. IL-6 knockout KO mice were compared with WT littermate mice in lean or obese conditions. IL-6 KO mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with the lean condition on a standard chow diet Overexpression of IL-6 was also used to test insulin resistance in mice.
In the study, IL-6 overexpression was generated in skeletal muscle, and the IL-6 protein levels were increased in the circulation. The mice lost both body weight and body fat in response to IL-6 in this model, even though their food intake remained unchanged These observations suggest that IL-6 increases energy expenditure.
In the IL-6 mice, insulin levels were elevated, and hypoglycemia was observed In another study, Sadagurski et al demonstrated that a high level of IL-6 in the circulation reduces obesity and improves metabolic homeostasis in vivo The role of the anti-inflammatory cytokine IL has been studied in the pathogenesis of obesity and insulin resistance IL is a critical cytokine of M2 type 2 macrophages.
A recent study has identified the roles of M1 pro-inflammatory and M2 anti-inflammatory macrophages in the regulation of insulin sensitivity An increase in M2 macrophages and a decrease in M1 macrophages within the adipose tissue are associated with enhanced insulin sensitivity.
In another study, the hematopoietic-cell-restricted deletion of IL in mice was used to study the relationship between IL and insulin resistance The mice were assessed for insulin sensitivity in an insulin tolerance test in lean chow diet and obese high fat diet conditions.
The results show that deletion of IL from the hematopoietic system does not have an effect on insulin resistance Other studies suggest that IL cannot improve insulin sensitivity in diet-induced obese mice or humans 90 , The antidiabetic drug thiazolidinedione TZD restores insulin action by activating PPARγ, thus lowering the levels of FFAs in the blood.
Activation of PPARγ improves insulin sensitivity in rodents and humans through a combination of metabolic actions, including partitioning of lipid stores and regulating metabolic and inflammatory mediators, termed adipokines However, TZD-based medicines for insulin sensitization have many side effects: troglitazone Rezulin was associated with massive hepatic necrosis; rosiglitazone Avandia and muraglitazone, with increased cardiovascular events; and now, pioglitazone has been associated with bladder cancer These adverse events suggest that the thiazolidinedione-based drugs may not be safe in the long-run.
It is necessary to discover a new class of drug to treat insulin resistance. Recent studies indicate that histone deacetylase HDAC inhibitors may be a new class of drug candidates for insulin sensitization. HDACs are key enzymes in regulating gene expression. Protein acetylation is one type of epigenetic regulation of gene expression.
Acetylation is controlled by histone acetyltransferases HATs and histone deacetylases HDACs. Histone acetylation by HATs opens the chromatin structure to activate gene transcription, while histone deacetylases HDACs repress gene expression.
HDACs are divided into three classes: class I HDACs 1, 2, 3, 8, 11 , class II HDACs 4, 5, 6, 7, 9, 10 94 and class III HDACs SIRT Inhibition of histone deacetylase activity has been reported as a new approach to treat diabetes mellitus 96 , 97 , In our study, supplementation of histone deacetylase inhibitors, butyrate or Trichostatin A, prevented high-fat diet-induced obesity and improved insulin sensitivity in mice.
HDAC inhibition promoted energy expenditure, and reduced blood glucose and triglyceride levels in mice HDAC inhibits insulin resistance on a molecular level by the following means: a reducing the lipid toxicity 44 , 99 , , , ; b reducing chronic systemic inflammation , , , , , ; c promoting beta-cell development, proliferation, differentiation and function 97 ; and d promoting energy expenditure 98 , Based on their multiple beneficial effects, HDAC inhibitors may represent a novel drug in the treatment of insulin resistance.
However, clinical trials are needed to test this concept. Type 2 diabetes is one of the major diseases associated with obesity. It is known that obesity promotes type 2 diabetes through insulin resistance, a state in which bodies lose their responsiveness to insulin. Many studies confirm that inflammation and free fatty acids FFAs are major pathogenic factors for insulin resistance in obese conditions.
The most effective therapy for insulin resistance is to reduce both FFA and inflammation. Diminishing inflammation by anti-inflammatory drugs does not significantly improve insulin sensitivity in animal models or in clinical trials because inflammation is beneficial in regulating energy metabolism.
Inhibiting this beneficial activity is likely to cause the failure of anti-inflammatory drugs in treating insulin resistance. Current literature consistently reports that fatty acids remain a therapeutic target in the treatment of insulin resistance.
As an insulin sensitization-drug, TZD reduces both FFA and inflammation in the body. However, TZDs have many side effects such as obesity, heart attacks, and bladder cancer. HDAC inhibitors may be a new class of drug for treating insulin resistance by promoting energy expenditure and preventing obesity.
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While studies have focused on the roles of intramyocellular lipids, mitochondrial defects, and endocrine effects of adipokines on SM insulin resistance 10 , 12 , 15 , emerging evidence indicates that inflammation also occurs in SM in the setting of obesity and may exert autocrine or paracrine effects on myocyte metabolic functions.
In this Review we focus on obesity-linked SM inflammation and its roles in muscle insulin resistance. Although obesity-linked inflammation is less well studied and documented in SM than in AT, available evidence suggests that SM myocytes can secrete large numbers of cytokines and other molecules and may become inflamed in obesity.
In addition, immune cells can infiltrate into SM and increase SM inflammation in obesity. SM as a secretory organ and myocyte secretion of inflammatory molecules. Similar to adipocytes, SM myocytes express and secrete numerous cytokines such as IL-6, IL-8, and IL and other molecules such as FGF21, irisin, myonectin, and myostatin known as myokines; see Table 1 and refs.
Whereas most adipokines are proinflammatory, regulated by obesity, and involved in the development of obesity-linked metabolic dysfunction 4 , 5 , 11 , most myokines are regulated mainly by exercise and muscle extraction, counteract the detrimental effects of adipokines, and have beneficial effects on glucose and lipid metabolism and inflammation 19 , Myokines may affect myocytes and immune cells locally via autocrine or paracrine actions and other cells such as adipocytes and hepatocytes via endocrine effects.
IL-6 is the most well-studied myokine. Exercise and muscle extraction dramatically enhance IL-6 secretion from muscle and can increase plasma IL-6 levels up to fold 19 — Acute treatment of myocytes or intravenous infusion of healthy humans with IL-6 increases basal and insulin-stimulated glucose uptake by myocytes and improves whole-body insulin sensitivity 19 , IL-6 also increases lipolysis and fatty acid FA oxidation in myocytes and adipocytes; induces UCP1 expression in mouse white AT, which is indicative of browning 20 , 22 — 25 ; and mediates antiinflammatory effects by inducing expression of antiinflammatory cytokines such as IL and inhibiting expression of proinflammatory cytokines such as TNF-α 19 , However, IL-6 is generally considered proinflammatory and can induce insulin resistance, particularly under chronic conditions related to obesity see below.
Irisin, another myokine enhanced by muscle contraction, may increase glucose transporter 4 GLUT4 expression and mitochondrial uncoupling and biogenesis in myocytes, and also induce browning of white AT 24 , 27 — Studies on the effects of obesity on myokine expression are limited and have had inconsistent results.
For example, obesity in rats decreased IL-6 and IL expression in SM Similarly, cultured myocytes from SM of obese subjects with impaired glucose tolerance or T2D expressed lower IL-6 levels than those from healthy controls However, more studies found increased IL-6 expression or release in SM of obese subjects with impaired glucose tolerance or T2D compared with healthy controls 32 — Differentiated myocytes can express numerous proinflammatory molecules Table 1 , particularly under stimulation of inflammatory cytokines and free FAs FFAs 32 , 34 — Differentiated cultured myocytes isolated from obese subjects with insulin resistance or T2D secrete more cytokines such as TNF-α and chemokines such as monocyte chemoattractant protein 1 MCP-1 than myocytes from lean controls 31 , 34 , Higher TNF-α levels were also observed in SM of rats fed a fructose-rich diet 39 , and TNF-α can induce insulin resistance and mitochondrial dysfunction in myocytes 40 — Thus, the obesity-linked increases in TNF-α secretion by myocytes may contribute to myocyte insulin resistance via autocrine effects.
Therefore, obesity is associated with increased inflammation in myocytes, which may secrete elevated levels of proinflammatory molecules and contribute to muscle inflammation.
Nevertheless, changes in myocyte secretion of cytokines do not appear to constitute the major component of SM inflammation in obesity see below , and the role of various myokines in SM inflammation remains to be further investigated. Infiltration of immune cells into SM.
Increased immune cell infiltration is the main characteristic of obesity-linked inflammation in AT 4 , 5 , 9 , 11 , 46 — Growing evidence indicates that immune cells also accumulate in SM and may constitute the predominant inflammatory cells in SM in obesity 2 , 11 , 35 , 52 , Increased macrophage and T cell levels have been reported in SM of obese humans with insulin resistance or T2D 35 — 37 , 53 — In fact, a short-term high-fat, high-calorie diet or overfeeding with induction of insulin resistance increased macrophage markers in SM in healthy subjects 56 , In mice, obesity and insulin resistance induced by a high-fat diet HFD was consistently associated with increased accumulation of immune cells including macrophages and T cells in SM 11 , 35 , 37 , 47 , 49 , 53 , 58 — Similar to humans, mice fed a short-term HFD have increased macrophage content in SM 35 , 53 , Mast cells and eosinophils were observed in mouse SM but showed no changes with obesity 53 , Changes in other immune cells including neutrophils, B cells, NK cells, and invariant NKT iNKT cells, which are found in visceral AT 2 , 13 , 64 , have not been reported in SM in the setting of obesity.
Both IMAT and PMAT are adjacent to myocytes and differ from subcutaneous AT Both are extramyocellular fat that expands substantially in obesity and decreases following weight loss 66 , and both depots are highly correlated with insulin resistance and expression of MCP-1 and C-reactive protein 65 , 67 — Macrophages and T cells within these adipose depots are markedly increased in obesity 35 , 49 , 53 and can form crown-like structures surrounding dead or dying adipocytes Additionally, macrophages and T lymphocytes can be found in SM between myofibers at a lower frequency 35 — 37 , Obesity-linked changes in immune cells and inflammatory markers are much greater in muscle AT than in muscle 35 , which may help explain the low levels of immune cells and inflammation in SM in human subjects with small-muscle biopsies 71 , as well as why alterations in BMI or lifestyle intervention—induced weight loss do not alter macrophage numbers in SM in obese subjects in some studies 72 , Similar to those in visceral AT, immune cells in SM tend to polarize into proinflammatory phenotypes in obesity.
While the proportion of IFN-γ—expressing Th1 cells is increased, the proportion of Tregs is decreased in SM in mice with obesity Accordingly, proinflammatory markers related to immune cell activation such as TNF-α, IL-1β, and IFN-γ are increased 32 , 33 , 35 , 37 , 47 , 53 , 58 , 60 , 61 , while antiinflammatory markers such as IL are reduced in SM in obesity Although in vitro studies show capacity of differentiated myocytes to express proinflammatory molecules 32 , 34 — 37 , studies in mouse models of obesity indicate that levels of most proinflammatory markers are much higher and show greater obesity-linked changes in PMAT than in muscle 35 , 37 , suggesting that in vivo obesity-linked SM proinflammatory molecules may be mainly derived from immune cells in muscle adipose depots.
Taken together, compelling evidence supports the association of obesity with increased inflammation in SM in both humans and rodents. Myocytes have the capacity to express cytokines and may secrete more proinflammatory cytokines in obesity. Inflammation in skeletal muscle in obesity.
A In lean conditions, few immune cells with resting or antiinflammatory phenotypes reside in skeletal muscle. At the same time, myocytes may become inflamed and express proinflammatory cytokines and chemokines.
C Chemokines and cytokines secreted by myocytes, adipocytes, and immune cells, along with FFAs that are transferred into skeletal muscle and ANG II produced within skeletal muscle, may themselves further accelerate immune cell recruitment and activation and myocyte inflammation, forming a feed-forward loop of inflammation in skeletal muscle.
Despite the evidence for increased SM inflammation in obesity, the underlying mechanisms remain largely unexamined. Below, we detail potential roles for various mediators in SM inflammation. Chemokines, adhesion molecules, and immune cell infiltration. Similar to what is observed in visceral AT 61 , 74 , 75 , inflammation, including immune cell infiltration, starts early in SM during obesity development 35 , 53 , 56 , 57 , Macrophage infiltration precedes T cell infiltration Infiltration of leukocytes from the circulation into tissues requires attractant signals such as chemokines, and chemokines such as MCP-1 increase early in SM and visceral AT of mice fed a HFD.
In visceral AT, the increase in MCP-1 appears to precede the increases in macrophages and the activation marker TNF-α 74 , 75 , suggesting that the initial increase in chemokines may derive from tissue-resident cells.
Adipocytes and myocytes, the main resident cells in AT and SM, respectively, can express chemokines including MCP-1 9 , 32 , 35 — 37 , Under stimulation with inflammatory molecules or FFAs or in obesity, adipocytes and myocytes secrete more chemokines 9 , 32 , 34 — 37 , 61 , which induce immune cell migration 9 , 37 , Therefore, chemokines secreted by myocytes or adipocytes may play crucial roles in immune cell infiltration and inflammation in SM and visceral AT.
MCP-1 overexpression in myocytes or adipocytes increases inflammation with enhanced immune cell infiltration in SM or visceral AT in mice 37 , 76 , while MCP-1 knockout prevents HFD-induced increases in muscle or AT macrophages The initiating signals that trigger SM or AT inflammation are not well known and may include FAs, particularly HFD-derived saturated FAs, which can induce expression of inflammatory molecules including chemokines in myocytes and adipocytes 34 , In addition to myocyte or adipocyte secretion of chemokines, as obesity progresses, recruited immune cells may also secrete chemokines, which may further increase inflammation in SM and AT.
The arachidonic acid—derived leukotriene LTB4, which is increased in SM, visceral AT, and liver of obese mice, also contributes to macrophage infiltration of visceral AT in obesity Interactions of adhesion molecules on immune cells and their ligands on endothelial cells are crucial for immune cell migration.
Lymphocyte function—associated antigen-1 LFA-1 , a β2 integrin mainly expressed on immune cells, plays an essential role in T cell accumulation and inflammation in SM and visceral AT of obese mice, likely by interacting with ICAM-1 on endothelial cells or antigen-presenting cells 35 , In the circulation, Ly-6C lo , but not Ly-6C hi , monocytes express CD11c 81 , In addition, macrophages and T cells proliferate in visceral AT 79 , 84 , 85 , and potential proliferation in SM warrants investigation.
Immune cell activation. Macrophages and T lymphocytes not only are increased in number but also display proinflammatory phenotypes in SM and visceral AT in obesity.
Cytokines and signaling pathways in immune cell activation. Cytokines play central roles in immune cell activation. IFN-γ and TNF-α are crucial for macrophage polarization into M1 proinflammatory phenotypes, while IL-4, IL, and IL are crucial for macrophage polarization into alternatively activated M2 phenotypes IL is critical for T cell polarization to Th1, whereas IL-4 is critical for T cell polarization to Th2 phenotypes.
TNF-α, the signature cytokine of M1-polarized macrophages, and IFN-γ, the signature cytokine of Th1, are both increased in SM and visceral AT in obesity and are involved in obesity-linked AT inflammation, including macrophage activation 35 , 58 , These cytokines may also induce immune cell activation and play crucial roles in muscle inflammation.
IL is reduced in SM in obesity, and overexpression of IL in SM attenuates obesity-induced macrophage activation in muscle The IKK complex, which consists of the catalytic subunits IKKα and IKKβ and the regulatory subunit IKKγ, activates NF-κB transcription activity by phosphorylating and degrading the inhibitory protein IκB.
Ablation of IKKβ in myeloid cells protects mice from obesity-induced inflammation Activation of NF-κB in obesity also leads to increases in IKKε, a non-canonical IKK, in macrophages, adipocytes, and liver.
Knockout or inhibition of IKKε in mice attenuates obesity-linked inflammation including reductions in accumulation and M1 polarization of macrophages in visceral AT and liver 89 , Obesity increases JNK activity in muscle and AT 89 , 91 and increases phosphorylated JNK levels in circulating monocytes Ablation of JNK1 alone or both JNK1 and JNK2 in hematopoietic cells or myeloid cells dramatically decreases obesity-induced inflammation in mice 92 , Tissue culture studies support a crucial role of JNK in macrophage polarization to M1, but not M2, phenotypes 47 , 92 , Upon binding its receptor, IFN-γ mainly activates JAK1 and JAK2, which phosphorylate and activate STAT1.
STAT1 plays a pivotal role in M1 polarization and Th1 polarization For example, knockout of LFA-1 in mice reduces obesity-induced T cell infiltration and Th1 polarization, along with decreased IFN-γ levels, but does not change total macrophage content, in SM and visceral AT.
However, macrophage expression of proinflammatory markers such as MCP-1 and TNF-α is decreased 35 , 79 , possibly because of reduced induction of macrophage activation by decreased Th1 cytokine in muscle. Moreover, MHC-II is upregulated on obese adipocytes, which also contribute to T cell activation in obese AT The potential role of these pathways in obesity-linked SM inflammation remains to be examined.
FFAs and signaling pathways in immune cell activation. In addition to increased cytokines, increased influx of FFAs derived from lipolysis in AT or from a HFD; see below usually occurs in SM in obesity.
FAs, particularly long-chain saturated FAs, have been consistently shown to induce inflammation, thereby also likely contributing to immune cell activation in SM in obesity.
Palmitic acid or a mixture of long-chain FAs increases macrophage expression of proinflammatory molecules and induces M1 polarization, possibly via engagement of TLR2 and TLR4 and subsequent activation of NF-κB and JNK pathways 47 , 92 , 93 , In addition, palmitic acid and its metabolite ceramide activate the NLRP3 inflammasome, a cytosolic multiprotein complex that activates caspase-1, leading to maturation and secretion of the proinflammatory cytokines IL-1β and IL Influx of FAs into SM and triglyceride-rich lipoproteins.
In obesity, elevated levels of circulating FFAs, mainly derived from lipolysis in adipocytes, lead to increased FA influx into SM, which not only induces inflammation in immune cells see above and myocytes in muscle, but also causes insulin resistance in myocytes see below.
In addition, obesity is usually associated with hypertriglyceridemia, with elevated levels of triglyceride-rich lipoproteins TGRLs , including enterocyte-derived chylomicrons and hepatocyte-derived VLDLs, which may also release more FAs into SM and contribute to muscle inflammation and insulin resistance.
Indeed, hypertriglyceridemia correlates with and may be a causal factor for insulin resistance and T2D Diets enriched with saturated fat or carbohydrates tend to cause increased levels of TGRLs Besides a diet high in saturated fat, a diet high in carbohydrates, particularly fructose, also induces inflammation in muscle 39 , In addition to the potential direct effect of high carbohydrates, elevated levels of TGRLs may contribute to muscle inflammation induced by a high-carbohydrate diet.
Under physiologic conditions, triglyceride in TGRLs is hydrolyzed by lipoprotein lipase LPL and releases FFAs, which are transferred into SM mainly as an energy source and into adipocytes, where they are re-esterified into triglyceride for storage Increased blood TGRL levels with no or modest changes in LPL activity; ref.
Indeed, obesity or muscle-specific overexpression of LPL increases muscle triglyceride content, with increased FA metabolites, including diacylglycerol DAG and ceramide, while muscle deletion of LPL decreases lipid content in SM — LPL-mediated lipid transfer appears to involve apolipoprotein E apoE , as apoE deficiency impairs FA delivery, leading to less lipid content and decreased inflammation in muscle The renin-angiotensin system in immune cell activation.
In addition to cytokines and FAs, the renin-angiotensin system RAS , which is activated locally in SM and AT and systemically in obesity , , has been involved in regulation of inflammation including immune cell inflammation — The classical RAS involves cleavage of angiotensinogen by renin in the circulation and formation of angiotensin I ANG I.
ANG I is converted to active ANG II by angiotensin-converting enzyme ACE , which is mainly expressed on endothelial cells in pulmonary circulation. The nonclassical RAS involves generation of ANG 1—7 from ANG I or II by ACE2 , By interacting with ANG II receptors ATRs , ANG II plays important roles in regulating blood pressure and fluid and electrolyte balance , In addition, ANG II plays pathologic roles in fibrosis, oxidative stress, and inflammation, which all occur in obesity, via hemodynamic blood flow reduction or non-hemodynamic effects , ANG II can induce activation of NF-κB, expression of MCP-1, TNF-α, and VCAM-1, and production of ROS which activates p38 MAPK in monocytes, endothelial cells, and cultured myocytes — , — ACE inhibitors and ATR blockers ARBs reduce inflammation, including SM and AT inflammation induced by obesity or fructose feeding 39 , , indicating a crucial role of ANG II in SM and AT inflammation in obesity.
In contrast, ANG 1—7 exerts cellular effects mainly through the Mas receptor , and has antiinflammatory effects including inhibition of macrophage infiltration and proinflammatory activation in AT induced by HFD or high-fructose diet , Local muscle inflammation may alter myocyte insulin sensitivity via paracrine or autocrine effects.
TNF-α or conditioned medium from Th1 cells or activated macrophages decreases myocyte insulin sensitivity 35 , 40 ,
Thank you for visiting nature. You are using Resisance browser resistwnce with limited support Insulun CSS. To obtain the Natural Coconut Oil experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Chronic inflammation occurs in obese conditions in both humans and animals. Below is a fesistance that is frequently asked by attendees Natural Coconut Oil Indulin program. How inflammatiion inflammation contribute Limitations of skinfold measurements Insulin resistance and inflammation resistance? Resisance time, poor diet Olive oil soap lifestyle, environmental toxins, and changes in the Gaming power renewal can contribute to systemic inflammation throughout the body. Firstly, inflammation within the skeletal muscle and adipose tissue can cause increased adiposity and risk of obesity, exacerbating the inflammatory cycle and affecting the regulation of myocyte metabolism and mitochondrial function. However, higher concentrations of inflammatory cytokines such as TNF-α inactivate IRS-1 which ultimately leads to impaired GLUT-4 translocation, further reducing insulin dependent transport of glucose to cells.
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