Subcutaneous fat and inflammation -
Louis and an investigator at the Istituto Superiore di Sanita, Rome, Italy. Increased IL-6 levels in the portal vein correlated with concentrations of an inflammatory substance called C-reactive protein CRP in the body. High CRP levels are related to inflammation, and chronic inflammation is associated with insulin resistance, hypertension, type 2 diabetes and atherosclerosis, among other things.
Klein, Fontana and J. Christopher Eagon, M. All were extremely obese, and all were undergoing gastric bypass surgery.
They took blood from the portal vein and from the radial artery in the arm and found differences in levels of IL-6 between the samples. Fontana believes the findings help explain how visceral fat can lead to inflammation, insulin resistance and other metabolic problems.
And he says by contributing to inflammation, visceral fat cells in the abdomen may be doing even more than that. There also is evidence that inflammation plays a role in cancer, and there is even evidence that it plays a role in aging.
Someday we may learn that visceral fat is involved in those things, too. Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes , published online Feb.
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Exercise effects on white adipose tissue: Beiging and metabolic adaptations. Diabetes 64 , — Download references. The authors thank Camilla Sørensen and Anja Jokipii for excellent technical assistance with preparation of the adipose tissue. Also, our deepest gratitude to professor Steen Seier Poulsen, who were instrumental in the immunhistochemical staining, and Ricardo Soares for helping out with the mRNA analysis.
The study was funded by the Nordea Foundation, The Novo Nordisk Foundation, Lundbeck Foundation, and Danish Council for Independent Research Health and Disease.
The Center for Physical Activity Research CFAS , Rigshospitalet, is supported by a grant from TrygFonden. Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Ziegler, A. Damgaard, A. Mackey, P. Schjerling, P. Magnusson, A. Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Physical Therapy, Musculoskeletal Rehabilitation Research Unit, Bispebjerg Hospital, Copenhagen, Denmark. The Centre of Inflammation and Metabolism and Centre for Physical Activity Research Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. You can also search for this author in PubMed Google Scholar. Ziegler A. planned the experiments.
Olesen A. designed the resistance adjusted running wheels. Damgaard A. and Ziegler A. obtained visceral fat tissue from the mice. L conducted anthropometric, immunohistochemically and immunofluorescence analysis.
Scheele C. established and analyzed mRNA expression in visceral adipose tissue. and Schjerling P. did all the statistical analysis. All authors edited the manuscript, but Ziegler A. and Kjær M. Correspondence to A. Open Access This article is licensed under a Creative Commons Attribution 4.
Reprints and permissions. An anti-inflammatory phenotype in visceral adipose tissue of old lean mice, augmented by exercise. Sci Rep 9 , Download citation. Received : 04 September Accepted : 07 August Published : 19 August Anyone you share the following link with will be able to read this content:.
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Abstract Visceral adipose tissue is an immunogenic tissue, which turns detrimental during obesity by activation of proinflammatory macrophages. Introduction Adipose tissue is host to various immune cells and it is well established that during obesity, the amount of inflammatory macrophages increase in adipose tissue 1 , 2.
Methods Exercise protocol Experiments were conducted in accordance with Danish guidelines Amendment of November 23, as approved by the Danish Animal Inspectorate, Ministry of Justice permit Table 1 Mice randomization and characteristics. Full size table. Table 2 Training intervention.
Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Data Availability All data are freely available upon request. References Xu, H. Article CAS Google Scholar Weisberg, S.
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Article Google Scholar Vieira, V. Article CAS Google Scholar Vissers, D. It is generally believed that the majority of WAT depots can develop browning under particular conditions, but more work is needed in this area. There is a growing list of physiological stressors that can promote the browning of WAT, including cold exposure, exercise, bariatric surgery, cancer cachexia, severe burns, as well as pharmacological and dietary components such as conjugated linoleic acid, short-chain fatty acids, capsaicin, non-caffeinated green tea extract, thiazolidinediones TZDs , and β-adrenergic receptors 41 — There is some debate regarding the origins of beige adipocytes, as well as their impact on energy homeostasis.
This theory suggests that dormant beige adipocytes can become quickly and readily activated when needed, reminiscent of an immune response. Beige adipocytes were initially thought to arise from transdifferentiation from white adipocytes, with the ability to de-differentiate back into white adipocytes 55 , Additional studies in vitro suggest that this is likely not the case The identity of committed beige adipocyte precursors has not been fully elucidated, but there is evidence from isolated WAT stromal cells that beige adipocyte precursors are distinct from white adipocyte precursors 36 , 39 , It has been suggested that strategies that increase the number of beige adipocytes in mouse WAT also protect them from diet-induced obesity 59 — Adipose tissue is an essential organ for the regulation of energy homeostasis.
Primarily tasked with storing excess energy as triglycerides, adipocytes undergo hyperplasia to increase the number of adipocytes and hypertrophy to increase the size of each adipocyte, allowing adipose tissue to expand in times of nutrient excess.
As needed, i. Stored triglycerides are therefore in a constant state of flux, whereby energy storage and energy mobilization are determined largely by hormonal fluctuations.
In healthy lean individuals, the majority of adipose tissue resides in subcutaneous depots, where it serves a thermoregulatory function, and from which stored triglycerides can be readily mobilized when needed Conditions that favor adipose tissue expansion, if endured chronically, will eventually exceed the storage capacity of defined adipose tissue depots, leading to the ectopic deposition of triglycerides in other tissues, including intra-abdominal depots discussed in more detail in later sections.
BAT plays an important role in thermoregulation in mammals, including adult humans BAT tissue is rich in mitochondria and uniquely expresses uncoupling protein-1 UCP-1 , which enables heat production by uncoupling ATP synthesis.
BAT-mediated thermogenesis has garnered substantial attention recently, as increasing BAT mass or activity could be an effective strategy to combat obesity. While the primary function of WAT is to manage energy storage, brown adipocytes efficiently burn fatty acids released from WAT during adaptive thermogenesis In addition, beige fat could also contribute to fat catabolism, potentially reducing WAT stores.
Human brown adipogenesis occurs in response to chronic or repeated cold stimulation, or in response to pharmacologic compounds such as beta adrenergic receptor β-AR agonists 68 , However, these browning-inducing methods mediated by the sympathetic nervous system are not practical as a weight loss strategy for several reasons: 1 the browning effects of cold exposure are rapidly reversible, 2 repeated cold exposure is too time- and energy-consuming to be a practical therapeutic, and 3 β-ARs promote adverse cardiometabolic events.
Therefore, mechanisms of WAT browning that are long lasting and act independently from the sympathetic nervous system are highly sought after. A new mechanism of WAT browning that does not involve the sympathetic nervous system SNS has recently been described.
Adipose tissue resident macrophages can secrete norepinephrine NE , the neurotransmitter that is also secreted by sympathetic neurons to activate BAT and WAT browning Several follow up studies have suggested that eosinophils, type 2 cytokines, and alternatively activated macrophages play critical roles in supporting WAT browning with concomitant increased energy expenditure and weight loss 71 — However, the notion that immune cells can influence WAT browning has recently been challenged, using different murine and in vitro approaches As such, there is some discordance regarding the role of macrophages in WAT browning, necessitating further studies.
Originally classified as a simple energy storage organ, adipose tissue is now known to function as a major endocrine system that secretes adipokines, growth factors, cytokines, and chemokines Adipokines are important mediators of various metabolic processes such as fatty acid oxidation, de-novo lipogenesis, gluconeogenesis, glucose uptake, insulin signaling, and energy expenditure in metabolically active tissues such as the liver, skeletal muscle, and brain The various adipokines secreted from adipose tissue and their functions will be described in more detail below.
The discussion will be limited to adipokines that are known to be produced to a large extent by adipocytes, in addition to other cell types within adipose tissue such as immune cells. Discovered in , leptin is a peptide hormone that is expressed exclusively by adipocytes and is essential for body weight regulation.
Leptin, adiponectin, and omentin the latter two will be described below are the only generally accepted adipokines with true endocrine function, meaning they are released from adipose tissue and exert effects on distant target organs. Leptin is encoded by the obesity gene ob.
Rodents and humans that lack either leptin or the leptin receptor LEPR are not only extremely obese, but are also hyperglycemic and extremely insulin resistant In lean and obese animals and humans, circulating leptin levels positively correlate with adiposity Prolonged fasting is associated with a sharp drop in plasma leptin levels, which drives food intake While leptin is expressed in all adipose depots, including BAT, its expression is highest in subcutaneous WAT As one of the first adipokines discovered in the mids 87 — 90 , adiponectin is a well-described insulin-sensitizing hormone that impacts a wide range of tissues.
Adiponectin is a distinctly unique adipokine, as its expression and circulating levels are inversely proportional to adiposity levels, in stark contrast to leptin. Adiponectin expression levels vary between sexes, with higher levels observed in females than males 91 — 93 , and between adipose tissue depots, with higher expression in subcutaneous than visceral WAT 94 , The insulin sensitivity-promoting properties of adiponectin are well-known, and are exemplified by the development of insulin resistance in adiponectin-deficient mice 96 , and the preservation of insulin sensitivity in adiponectin-overexpressing mice Adiponectin signals through two related receptors, ADIPOR1 and ADIPOR2, followed by docking of the adaptor protein APPL1 The resulting signaling pathway, mediated through peroxisome proliferator-activated receptor alpha PPARα , leads to metabolic improvements involving decreased hepatic gluconeogenesis, increased liver and skeletal muscle fatty acid oxidation, increased glucose uptake in skeletal muscle and WAT, and decreased WAT inflammation Thus, adiponectin receptors are highly expressed in skeletal muscle, liver, and adipose tissue.
In addition, adiponectin receptors are expressed in the pancreas, where adiponectin functions to mitigate β-cell loss by neutralizing inflammatory and lipotoxic ceramides and diacylglycerols In addition to β-cells, adiponectin has also been shown to exhibit strong anti-inflammatory effects on other cell types such as macrophages and fibrogenic cells 99 , , Taken together, adiponectin plays a protective role in mitigating features of the metabolic syndrome.
Resistin is a polypeptide that is secreted by obese adipose tissue. It was originally described as an adipocyte-specific hormone, but it is now thought to originate from macrophages residing in inflamed adipose tissue in mice and from circulating monocytes and tissue macrophages in humans , Evidence for this comes from an initial study in which it was observed that plasma resistin levels are elevated in a diet-induced obese mouse model, that blocking resistin action using a neutralizing antibody improves insulin sensitivity, and that recombinant resistin administration to healthy mice promotes insulin resistance These initial studies led to the suggestion that resistin plays an important role in modulating insulin resistance in the context of obesity, and it has been shown to correlate with insulin resistance in mice and humans Plasma resistin levels have been shown to be increased in obese animal models and humans — and to decrease with weight loss in humans Conversely, some studies have shown that adipose tissue-derived resistin is suppressed in obesity — , inciting the controversy over what role resistin plays in obesity that persists today.
Evidence suggests that visceral fat is the largest contributor to circulating resistin levels , supporting the case for an association between resistin and insulin resistance. Moreover, resistin is believed to be an active participant in propagating inflammatory responses. Resistin can upregulate inflammatory cytokines such as TNFα and IL-6 in monocytes and macrophages in a nuclear factor kappa-B NFκB -dependent manner , and is positively associated with circulating inflammatory markers such as C-reactive protein CRP and TNFα Thus, while resistin is an established adipokine and has been shown in some cases to be associated with adverse health conditions such as obesity and insulin resistance, a clear role for resistin is still under active investigation.
Initially described as an adipokine secreted from omental WAT , it is now generally accepted that omentin is also expressed in other WAT depots such as epicardial fat, and that it derives specifically from the stromal vascular fraction of WAT , Omentin is a true endocrine hormone that circulates in the blood , Omentin levels are reduced in subjects with obesity and T2DM , , leading investigators to speculate that omentin may be involved in glucose homeostasis.
Indeed, studies using in vitro models showed that omentin enhances insulin-stimulated glucose uptake in human adipocytes by activating Akt signaling pathways , and studies in humans show a significant negative correlation between serum omentin levels as well as adipose omentin mRNA levels with insulin resistance , , Omentin levels have been shown to gradually increase in response to weight loss , Additional studies suggest that omentin has anti-inflammatory properties.
Omentin blunts cytokine expression in endothelial cells , vascular smooth muscle cells , , macrophages , cardiomyocytes , and adipose tissue itself , and is negatively associated with systemic inflammatory markers such as TNF and IL-6 Thus, omentin is considered to be a biomarker for metabolic health that may function to blunt obesity-related cytokine effects FGF21 is an endocrine hormone that is involved in the regulation of lipid, glucose, and energy homeostasis FGF21 has received a lot of attention for its insulin-sensitizing and weight loss-inducing effects when administered pharmacologically The liver is the primary source of circulating FGF21, induced by metabolically stressful conditions such as fasting, a ketogenic diet, protein restriction, and bariatric surgery , while the brain and adipose tissue are primary FGF21 targets , Other tissues are known to also secrete FGF21, including the pancreas and skeletal muscle , However, under certain metabolic conditions such as obesity, WAT and BAT may also produce FGF21 This is supported by several studies showing that BMI and adiposity positively correlate with circulating FGF21 levels in mice and humans — It is clear that FGF21 levels become elevated as obesity develops in mice and humans, and are positively correlated with BMI, adiposity, and FGF21 expression levels in adipose tissue — While many studies have shown that adipose tissue expresses FGF21 in rodents , — , there is still some debate about whether FGF21 is readily expressed in human adipose tissue.
There are a handful of studies that suggest that adipose tissue FGF21 mRNA expression is below detection levels or not expressed by adipose tissue However, numerous additional studies have found detectable FGF21 mRNA expression in visceral WAT , , subcutaneous WAT , , , epicardial WAT , cervical adipose tissue , , and PVAT , , with the latter two depots containing both WAT and BAT.
FGF21 protein has also been detected in adipose tissue by Western blot and immunohistochemistry Some studies suggest that adipose-derived FGF21 is a marker of metabolic stress, as it has been shown to correlate with features of the metabolic syndrome , , Regardless, a clearly-defined function of adipose-derived FGF21 has not yet been established, nor whether adipose-derived FGF21 promotes primarily local effects or contributes to the circulating FGF21 pool under particular metabolic conditions.
Elegant studies using tissue-specific Fgf21 KO mice show that adipocyte-derived Fgf21 is not involved in obesity-associated insulin resistance, and that adipose-derived Fgf21 doesn't circulate, instead acting in a paracrine fashion However, the mice used in that study were fasted for 24 h, introducing a metabolic stress that would likely only induce liver-derived Fgf21 that may have masked any contribution from adipose-derived Fgf In later studies, a thermogenic role for adipose-derived Fgf21 has been described, in which the browning of WAT was shown to require adipocyte-Fgf21 , Thus, it is possible that hepatic- and adipose-derived FGF21 are induced by different stimuli, and that more studies are required to conclusively define a role for adipose-derived FGF Obesity results when energy intake chronically exceeds energy expenditure.
Many factors are involved, including genetic, epigenetic, hormonal, and lifestyle factors that are beyond the scope of this review. Adipocyte number is believed to be tightly regulated and determined during childhood However, during the development of obesity, adipose tissue can expand by either hypertrophy an increase in adipocyte size or hyperplasia an increase in adipocyte number due to the recruitment of new adipocytes.
Obesity is characterized by dysfunctional adipose tissue, in which adipocytes initially become hypertrophic during periods of caloric excess and secrete adipokines that result in the recruitment of additional pre-adipocytes, which differentiate into mature adipocytes as compensatory protection against some of the adverse metabolic consequences of obesity This concept is supported by observations in AdipoChaser mice, a model for tracking adipogenesis AdipoChaser mice fed a high fat diet display evidence of hypertrophy of visceral WAT within 1 month, while hyperplasia occurs after 2 months.
Importantly, subcutaneous WAT does not undergo hyperplasia, and hypertrophy lags behind the visceral compartment, with evidence of subcutaneous WAT hypertrophy after 2 months of high fat feeding However, when the capacity for adipocyte recruitment and hypertrophy is overwhelmed, fat accumulates in ectopic sites such as visceral depots, the liver, skeletal muscle, and pancreatic beta cells.
These changes are accompanied by inflammation, insulin resistance and other features of the metabolic syndrome, and have been termed metabolically unhealthy obesity MUHO , In contrast to MUHO, some people accumulate fat mainly in subcutaneous depots, a condition that has been termed metabolically healthy obesity MHO.
MHO is not accompanied to any great extent by insulin resistance, adipose tissue and systemic inflammation, and other features of the metabolic syndrome such as dyslipidemia and hypertension — Thus, the distribution of fat accumulation is a major determinant of metabolic complications associated with obesity, which can increase the risk of CVD.
Various features that contribute to dysfunctional WAT in obesity will be discussed in the sections that follow. A sub-group of obese individuals remain insulin-sensitive, and exhibit normal metabolic and hormonal profiles despite having a BMI that would characterize them as obese , Therefore, MHO individuals have a lower risk for developing T2DM and cardiovascular disease MHO is sometimes defined as having 2 or less features of the metabolic syndrome or based on homeostatic model assessment of insulin resistance HOMA-IR measures, but consensus on a precise definition does not exist Thus, some individuals classified as having MHO rather fall somewhere between metabolically healthy and unhealthy.
Moreover, individuals with so-called MHO can progress to develop features of the metabolic syndrome with time — Because CVD outcomes in general relate to the number of metabolic abnormalities present in individuals with MUHO — , there is less CVD in individuals with MHO than those with the metabolic syndrome.
In addition, while MHO individuals are so defined due to a healthier cardiometabolic profile than those with MUHO, the true clinical benefits of MHO remain in question, as the cardiometabolic profile and insulin sensitivity of MHO individuals typically does not improve significantly with weight loss , — Nevertheless, evidence from animal models and cultured adipocytes do suggest that the preservation of the capacity for subcutaneous WAT expansion mitigates extensive visceral and hepatic fat accumulation, potentially driving the MHO phenotype 76 , 97 , Other obese individuals tend to accumulate fat mainly intra-abdominally in visceral depots, which is also known as central obesity.
Visceral adiposity is associated with insulin resistance, a predisposition to diabetes, local and systemic inflammation, dyslipidemia [characterized by hypertriglyceridemia, a preponderance of small, dense low-density lipoprotein LDL particles and reduced high-density lipoprotein HDL -cholesterol levels], insulin resistance, dysglycemia [a broad term that refers to an abnormality in blood sugar stability], adipose tissue and systemic inflammation, hypertension, a thrombogenic profile and non-alcoholic fatty liver disease NAFLD This constellation of CVD risk factors associated with visceral obesity is widely known as the metabolic syndrome and is a hallmark of MUHO, illustrated in Figure 1.
Visceral obesity and the metabolic syndrome are associated with an increased risk of developing CVD, which is exacerbated when overt diabetes develops as a result of insulin secretion failing to adequately compensate for insulin resistance.
Interestingly, even normal weight individuals who accumulate fat intra-abdominally have these metabolic abnormalities , , including an increased risk of CVD. Asians and Asian-Americans are particularly prone to accumulate intra-abdominal fat and have features of the metabolic syndrome despite having normal weights and BMI values by Western standards , raising the question of whether different normal values should apply to individuals of Asian ancestry.
These indexes are notable for their inclusion of upper subcutaneous WAT, which some consider to contribute as much, if not more, to metabolic syndrome than visceral WAT alone CT scanning at the level of the umbilicus has been found to be useful but is expensive and not practical other than for research purposes at present.
Lower body subcutaneous WAT does not correlate with risk factors for the metabolic syndrome, potentially due to a slower FFA turnover, higher levels of adipocyte hyperplasia, and lower levels of inflammation — Figure 1. Metabolically healthy obesity MHO vs. metabolically unhealthy obesity MUHO.
In comparison with lean metabolically healthy subjects, those with MHO have increased adiposity and BMI, but with reduced systemic inflammation and retained insulin sensitivity, thus defining them as not having metabolic syndrome MetS.
MHO subjects have elevated subcutaneous white adipose tissue WAT levels, without excessive accumulation of visceral fat. Their adipokine profile is similar to lean subjects, but with increased leptin, resistin, and FGF21, and decreased adiponectin, which limits their risk of developing type 2 diabetes mellitus T2DM and cardiovascular disease CVD in the short term.
By contrast, those with MUHO exhibit elevated insulin resistance and systemic inflammation in addition to increased adiposity and BMI over lean controls, contributing to MetS.
MUHO individuals have excess subcutaneous and intra-abdominal adipose tissue, with increased hepatic fat and fat distributed amongst other visceral organs. This leads to a dysfunctional adipokine profile, characterized by reduced adiponectin and omentin, with further elevated leptin, resistin, FGF21, and cytokines when compared to lean controls.
Thus, MUHO subjects are at risk for developing T2DM and CVD. Notable differences in the adipokine profile between MHO and MUHO subjects have been reported, which could contribute to their respective risks for T2DM and CVD.
Leptin has been shown to be higher in MUHO than MHO obese Chinese children in one study , but was not found to differ between adult groups in several other studies — By contrast, adiponectin has consistently been shown to be higher in subjects with MHO than in those with MUHO, despite both populations having lower adiponectin than metabolically healthy lean controls , — Resistin and FGF21 levels tend to be highest in the MUHO population , Data on whether omentin levels differ between MHO and MUHO has been inconsistent, with one study suggesting that MUHO subjects have higher omentin levels than MHO subjects , and other suggesting the opposite, that omentin levels are negatively correlated with the metabolic syndrome , Cytokines such as TNFα and IL-6 as well as the chemokines SAA and MCP-1 have been shown to be elevated in MUHO These adipokine differences between subjects with MHO and MUHO are depicted in Figure 1.
Adipose tissue expansion in obesity is accompanied by inflammatory changes within adipose tissue, contributing to chronic low-grade systemic inflammation that is characterized as mildly elevated levels of circulating cytokines, chemokines, and acute phase reactants.
Expansion of adipose tissue depots during weight gain is accompanied by an infiltration of new inflammatory cells, the major one initially being macrophages. These pro-inflammatory cells are recruited in response to chemokines such as monocyte chemotactic protein-1 MCP-1 produced by hypertrophic adipocytes , Studies in mice have demonstrated that most macrophages in obese adipose tissue are derived from circulating monocytes , although a small percentage appear to derive from proliferation of resident tissue macrophages These anti-inflammatory macrophages are believed to be responsible for maintaining tissue homeostasis It remains unclear whether the derivation of adipose tissue macrophages is the same in human obesity.
Macrophage accumulation occurs to a greater extent in visceral than in subcutaneous adipose depots in both rodents and humans — Macrophages are seen in crown-like clusters, where they are thought to represent an immune response to dead and dying adipocytes However, use of genetic markers show that these cells have significant differences from classical M1 macrophages and alternate nomenclatures have been suggested for these pro-inflammatory cells.
Morris and Lumeng have divided adipose tissue macrophages into several populations based on cell surface markers and expression profiling Using a proteomics approach, Kratz et al.
showed that markers of classical activation were absent on ATMs from obese humans. Such markers of metabolic activation were expressed by pro-inflammatory macrophages in adipose tissue from obese humans and mice and correlated with the extent of adiposity In addition to macrophages, T-cells also are present in normal adipose tissue and demonstrate phenotypic change during weight gain.
Th2 cytokines e. With weight gain in mice there is a shift away from a predominance of TH2 T cells present in lean adipose tissue and toward more TH1 and cytotoxic T cells as well as a reduction in regulatory T cells Tregs Interferon γ IFNγ —expressing Th1 polarized T cells appear to promote adipose tissue inflammation and increased IFN-γ activity has been reported in adipose tissue in both mice and humans , A subset of T cells called natural killer T NKT cells respond to lipid or glycolipid antigens — The number of invariant NKT iNKT numbers has been observed to be reduced in adipose tissue and livers from obese mice and humans — B-cells and mast cells also are increased in adipose tissue in the obese state , , Use of specific cell surface markers has also demonstrated the presence of dendritic cells in adipose tissue, and studies indicate that dendritic cells are independent contributors to adipose tissue inflammation during obesity , There is good evidence to support the notion that the systemic inflammation that is associated with obesity and contributes to insulin resistance begins with adipose tissue inflammation.
The regulation of hepatic C-reactive protein CRP and serum amyloid A SAA is likely in response to IL-6 secretion from visceral adipose tissue that directly targets the liver via the portal circulation — CRP is a prominent biomarker for insulin resistance and CVD — , and SAA antagonizes insulin action in adipocytes, thus contributing to systemic insulin resistance SAA also has been associated with CVD in some rodent and human models , — In summary, the discovery of elevated secretion of inflammatory cytokines by obese adipose tissue provides evidence that obesity directly mediates systemic inflammation, which contributes to insulin resistance and CVD discussed further in later sections.
Obesity is associated with elevated circulating levels of IL-6 and TNFα, which are subsequently decreased with weight loss , Adipose tissue is a major source of these cytokines as well as the chemokine MCP-1, which is important for recruitment of inflammatory cells such as macrophages to expanding adipose tissue While such inflammatory mediators that originate from adipose tissue could technically be classified as adipokines, they are also produced by the majority of cell types in the body and will therefore be described in further detail in this section.
It should be noted that cytokine and chemokine production is limited in lean adipose tissue and in subjects with MHO. Many cell types synthesize and secrete these cytokines and chemokines, including several that make up the adipose tissue milieu such as monocytes, macrophages, dendritic cells, B cells, and T cells.
As such, they play a prominent role in adipose tissue pathophysiology associated with obesity. Much research has been devoted to the role that adipose-derived IL-6 plays in the etiology of obesity.
The expansion of adipose tissue is accompanied by excessive adipocyte lipolysis and subsequently elevated FFA levels, which promotes adipocyte IL-6 secretion , Omental fat produces 2 to 3-fold higher levels of IL-6 than subcutaneous fat , providing a potential mechanism for the higher contribution of omental WAT to insulin resistance Most studies in vitro and in mice suggest that adipose-derived IL-6 promotes hepatic insulin resistance and glucose intolerance , , , while some indicate that in certain contexts IL-6 signaling in WAT and liver may be protective against metabolic disease , For example, mice with genetic disruption of the IL-6 receptor specifically in the liver exhibit exacerbated hepatic inflammation and impaired glucose tolerance , suggesting that IL-6 may also function to limit hepatic inflammation.
Thus, the context in which IL-6 signaling is studied is critically important for the interpretation of its function. In addition to its secretion from inflammatory cells such as monocytes and macrophages, TNFα was first described as an adipokine in As with IL-6, TNFα levels positively correlate with adiposity, BMI, insulin levels, and insulin resistance , While adipocytes themselves can secrete TNFα, the majority of TNFα secreted from adipose tissue is derived from immune cells in the stromal vascular fraction, and that obesity-associated increases in TNFα largely reflect the infiltration of pro-inflammatory macrophages within expending adipose tissue One mechanism by which adipose-derived TNFα may promote insulin resistance is by directly activating hormone sensitive lipase HSL , thereby increasing FFA release from adipocytes which promotes insulin resistance in the liver and skeletal muscle Another mechanism is via autocrine activation of insulin receptor substrate-1 IRS-1 , which prevents insulin from interacting with its receptor Monocyte chemotactic protein-1 MCP-1 is a potent chemotactic factor that promotes monocyte and macrophage recruitment into sites of inflammation during tissue injury and infection.
It is secreted by adipocytes during the development of obesity and leads to infiltration of monocytes, which differentiate to become adipose tissue macrophages. The macrophages in turn secrete additional MCP-1 leading to further recruitment of inflammatory cells , Body mass index and adiposity strongly correlate with adipose CCL2 the gene encoding MCP-1 expression levels, and MCP-1 decreases following weight loss in humans In addition, mice engineered to express elevated levels of Ccl2 specifically from adipocytes exhibit increased macrophage recruitment into adipose tissue, and subsequently increased insulin resistance, effects that were not observed in diet-induced obese mice that were deficient in Ccl2 Evidence suggests that human visceral WAT secretes higher levels of MCP-1 than subcutaneous WAT These studies and others have prompted the suggestion that MCP-1 could be a viable therapeutic target for the treatment of obesity and associated insulin resistance.
While well-described as an acute phase protein secreted by the liver in response to pro-inflammatory cytokines, SAA is also expressed in adipocytes and macrophages and correlates with adiposity , — There are 4 subtypes of SAA: SAA1—4.
SAA1 and SAA2 are highly upregulated in response to inflammation, while SAA4 is largely constitutively expressed. SAA3 is a pseudogene in humans, replaced by SAA1 and SAA2 in extra-hepatic tissues.
While the best defined cell source of SAA1 and SAA2 is hepatocytes, SAA1 and SAA2 are also expressed from adipocytes and macrophages under inflammatory conditions in metabolic diseases such as obesity, insulin resistance, and cardiovascular disease SAA3 expression is increased during hypertrophy of cultured mouse adipocytes and in gonadal fat in obese mice , Inducible forms of SAA also are expressed in both subcutaneous and omental WAT from obese humans.
Thus, the increased adipocyte size and number that accompanies obesity is also associated with elevated adipose tissue-derived SAA levels, likely in part due to increased hepatic secretion in response to cytokines produced in adipose tissue.
In obesity, white adipose tissue may become dysfunctional and unable to properly expand to store excess ingested energy, triggering storage of triglycerides in sites where the primary function is not fat storage. Excessive amounts of visceral fat also is considered to be a form of ectopic fat, and as noted earlier, is associated with features of the metabolic syndrome and an increased risk of T2DM and cardiovascular complications In animal models as well as in humans, it has been shown that the accumulation of lipotoxic diacylglycerols DAGs and ceramide, as occurs with visceral obesity, leads to impaired insulin signaling and reduced glucose uptake in skeletal muscle and liver — More specific mechanisms by which ectopic fat accumulation in particular tissues promotes insulin resistance will be explained in the following sections.
Several studies have reported an inverse relationship between hepatic lipid content and whole-body insulin sensitivity — The liver is a major target for the excessively produced inflammatory cytokines and FFAs released from obese WAT see later. FFA-derived triglycerides accumulate in the cytoplasm of hepatocytes in the form of lipid droplets.
While the lipid droplets may not be lipotoxic per se , various intermediate lipid moieties generated during triglyceride synthesis e. Selective upregulation of ceramide degradation pathways in the liver has been shown to reverse hepatic lipid accumulation and improve glucose tolerance in diet-induced obese mice Moreover, obesity-associated reductions in adiponectin have also been shown to contribute to hepatic steatosis, presumably by blunting hepatic fatty acid oxidation, a process regulated by adiponectin — It also has been suggested that adipose tissue inflammation contributes to hepatic lipid accumulation.
Kanda et al. showed that overexpressing Ccl2 from adipocytes in mice led to macrophage accumulation in adipose tissue and subsequent hepatic steatosis and hepatic insulin resistance, without an obese phenotype Similarly, mice in which Ccl2 had been deleted showed resistance to high fat diet-induced insulin resistance and hepatic steatosis, an effect that was accompanied by reduced expression of TNFα in adipose tissue Additional evidence to support the notion that adipose tissue inflammation promotes hepatic steatosis derives from studies showing that adipose-derived cytokines promote lipolysis of WAT stores , , thus increasing circulating FFA levels.
In the healthy liver, the role of Kupffer cells is to phagocytose pathogens and toxins and to maintain tissue homeostasis and repair, akin to an M2 macrophage , The primary stimuli for Kupffer cell activation likely derive from dysfunctional adipose tissue, including FFA, cytokines, and adipokines Adipokine imbalance such as the hypoadiponectinemia that results from visceral adipose tissue expansion fails to suppress hepatic inflammation and oxidative stress, contributing to Kupffer cell activation.
Thus, signals from dysfunctional obese adipose tissue propagate hepatic inflammation by activating resident Kupffer cells, which then themselves secrete pro-inflammatory cytokines, further amplifying systemic inflammation Lipids also can be stored within skeletal muscle when the capacity for fat storage by WAT is exceeded Lipids can be stored either between muscle fibers as adipocytes, or extramyocellular lipids , or within muscle cells cytosolic triglycerides, or intramyocellular lipids Pre-adipocytes have been identified within skeletal muscle, providing evidence that distinct adipocyte cells may reside between skeletal muscle fibers There is an association between ectopic skeletal muscle fat and insulin resistance that is largely dependent on BMI, but this association persists when BMI is statistically accounted for —
Current address: Department of Laboratory Medicine, University of Control portion sizes with appetite suppressant, San Francisco, Red pepper snapper Francisco, Fay. designed and planned the study. performed experiments supervised by J. performed flow cytometry experiments. performed experiments and analyzed and interpreted data. composed figures, and J. wrote the manuscript.Subcutaneous fat and inflammation -
Gollisch, K. Effects of exercise training on subcutaneous and visceral adipose tissue in normal- and high-fat diet-fed rats. AJP Endocrinol. Craig, B. Adaptation of fat cells to exercise: response of glucose uptake and oxidation to insulin. Mathur, N. Exercise as a mean to control low-grade systemic inflammation.
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Exercise effects on white adipose tissue: Beiging and metabolic adaptations. Diabetes 64 , — Download references. The authors thank Camilla Sørensen and Anja Jokipii for excellent technical assistance with preparation of the adipose tissue. Also, our deepest gratitude to professor Steen Seier Poulsen, who were instrumental in the immunhistochemical staining, and Ricardo Soares for helping out with the mRNA analysis.
The study was funded by the Nordea Foundation, The Novo Nordisk Foundation, Lundbeck Foundation, and Danish Council for Independent Research Health and Disease. The Center for Physical Activity Research CFAS , Rigshospitalet, is supported by a grant from TrygFonden.
Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Ziegler, A.
Damgaard, A. Mackey, P. Schjerling, P. Magnusson, A. Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Healthy and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Physical Therapy, Musculoskeletal Rehabilitation Research Unit, Bispebjerg Hospital, Copenhagen, Denmark.
The Centre of Inflammation and Metabolism and Centre for Physical Activity Research Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
You can also search for this author in PubMed Google Scholar. Ziegler A. planned the experiments. Olesen A. designed the resistance adjusted running wheels. Damgaard A. and Ziegler A. obtained visceral fat tissue from the mice. L conducted anthropometric, immunohistochemically and immunofluorescence analysis.
Scheele C. established and analyzed mRNA expression in visceral adipose tissue. and Schjerling P. did all the statistical analysis. All authors edited the manuscript, but Ziegler A. and Kjær M. Correspondence to A.
Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. An anti-inflammatory phenotype in visceral adipose tissue of old lean mice, augmented by exercise. Sci Rep 9 , Download citation.
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nature scientific reports articles article. Download PDF. Subjects Ageing Chronic inflammation Fat metabolism. Abstract Visceral adipose tissue is an immunogenic tissue, which turns detrimental during obesity by activation of proinflammatory macrophages. Introduction Adipose tissue is host to various immune cells and it is well established that during obesity, the amount of inflammatory macrophages increase in adipose tissue 1 , 2.
Methods Exercise protocol Experiments were conducted in accordance with Danish guidelines Amendment of November 23, as approved by the Danish Animal Inspectorate, Ministry of Justice permit Table 1 Mice randomization and characteristics.
Full size table. Table 2 Training intervention. Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Data Availability All data are freely available upon request. References Xu, H. Article CAS Google Scholar Weisberg, S. Article CAS Google Scholar Hotamisligil, G. Article ADS CAS Google Scholar Fontana, L.
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As scientists learn more about the key Unique weight loss of inflammatioh in diabetes, heart disease and other disorders, new research from Foam rolling for recovery University School of Control portion sizes with appetite suppressant in St. Louis suggests that fat inflammstion the belly may be an imflammation promoter of that inflammation. Excess fat is known to be associated with disease, but now the researchers have confirmed that fat cells inside the abdomen are secreting molecules that increase inflammation. For years, scientists have been aware of a relationship between disease risk and excess belly fat. During medical exams, some physicians measure waist circumference to identify patients at increased risk for these problems. Not just any belly fat will cause inflammation, however. Birgitta W. Cat der KolkMarianthi KalafatiMichiel Managing inflammation through exerciseMarleen M. van SubutaneousNicole VogelzangsWim H. SarisArne AstrupArmand ValsesiaDominique LanginCarla J. van der KallenSimone J. EussenCasper G.
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