Recent advances in the relationship between obesity, inflammation, and insulin resistance

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.     

Interleukin-7 regulates adipose tissue mass and insulin sensitivity in high-fat diet-fed mice through lymphocyte-dependent and independent mechanisms

Although interleukin (IL)-7 is mostly known as a key regulator of lymphocyte homeostasis, we recently demonstrated that it also contributes to body weight regulation through a hypothalamic control. Previous studies have shown that IL-7 is produced by the human obese white adipose tissue (WAT) yet its potential role on WAT development and function in obesity remains unknown. Here, we first show that transgenic mice overexpressing IL-7 have reduced adipose tissue mass associated with glucose and insulin resistance. Moreover, in the high-fat diet (HFD)-induced obesity model, a single administration of IL-7 to C57BL/6 mice is sufficient to prevent HFD-induced WAT mass increase and glucose intolerance. This metabolic protective effect is accompanied by a significant decreased inflammation in WAT. In lymphocyte-deficient HFD-fed SCID mice, IL-7 injection still protects from WAT mass gain. However, IL-7-triggered resistance against WAT inflammation and glucose intolerance is lost in SCID mice. These results suggest that IL-7 regulates adipose tissue mass through a lymphocyte-independent mechanism while its protective role on glucose homeostasis would be relayed by immune cells that participate to WAT inflammation. Our observations establish a key role for IL-7 in the complex mechanisms by which immune mediators modulate metabolic functions.     

Hydrodynamic delivery of IL-38 gene alleviates obesity-induced inflammation and insulin resistance

Obesity is associated with a chronic inflammatory response. Interleukin (IL)-38 is a poorly characterized cytokine of the IL-1 family with anti-inflammatory activity. The role of IL-38 in obesity-induced inflammation and insulin resistance remains unknown. In this study, we investigated the effects of IL-38 expression by hydrodynamic-based gene delivery on high-fat diet-induced obesity in mice. Transfer of plasmid DNA encoding IL-38 reduced weight gain, liver fat content, adipose tissue weight, and obesity-induced insulin resistance compared with administration of a control plasmid. Moreover, IL-38 gene delivery inhibited the production of inflammatory mediators including IL-1β, IL-6, and monocyte chemotactic protein-1. These results suggest that IL-38 is a potential new target for the treatment of obesity.     

The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer

Recent discoveries involving the cytokine interleukin (IL)-6 have originated from diverse disciplines, revealing roles in biological processes that are likewise varied. The most novel findings suggest a connection between inflammation and diseases, such as insulin resistance associated with diabetes mellitus and cancer, which had not or only weakly been appreciated previously. The IL-6 pathway is one of the mechanisms linking inflammation to these disease processes. In addition, new evidence points toward IL-6 as one of the mediators coordinating the interface between adaptive and innate immunity. Here, we review the evidence linking IL-6 to inflammatory diseases and cancer.     

Differential expression and localization of 12/15 lipoxygenases in adipose tissue in human obese subjects

Adipose tissue inflammation in obesity is a major factor leading to cardiovascular disease and type 2 diabetes.12/15 lipoxygenases (ALOX) play an important role in the generation of inflammatory mediators, insulin resistance and downstream immune activation in animal models of obesity. However, the expression and roles of 12/15ALOX isoforms, and their cellular sources in human subcutaneous (sc) and omental (om) fat in obesity is unknown. The objective of this study was to examine the gene expression and localization of ALOX isoforms and relevant downstream cytokines in subcutaneous (sc) and omental (om) adipose tissue in obese humans. Paired biopsies of sc and om fat were obtained during bariatric surgeries from 24 morbidly obese patients. Gene and protein expression for ALOX15a, ALOX15b and ALOX 12 were measured by real-time PCR and western blotting in adipocytes and stromal vascular fractions (SVF) from om and sc adipose tissue along with the mRNA expression of the downstream cytokines IL-12a, IL-12b, IL-6, IFNγ and the chemokine CXCL10. In a paired analysis, all ALOX isoforms, IL-6, IL-12a and CXCL10 were significantly higher in om vs. sc fat. ALOX15a mRNA and protein expression was found exclusively in om fat. All of the ALOX isoforms were expressed solely in the SVF. Further fractionation of the SVF in CD34+ and CD34- cells indicated that ALOX15a is predominantly expressed in the CD34+ fraction including vascular and progenitor cells, while ALOX15B is mostly expressed in the CD34- cells containing various leucocytes and myeloid cells. This result was confirmed by immunohistochemistry showing exclusive localization of ALOX15a in the om fat and predominantly in the vasculature and non-adipocyte cells. Our finding is identifying selective expression of ALOX15a in human om but not sc fat. This is a study showing a major inflammatory gene exclusively expressed in visceral fat in humans.     

SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice

SOCS (suppressor of cytokine signaling) proteins are inhibitors of cytokine signaling involved in negative feedback loops. We have recently shown that insulin increases SOCS-3 mRNA expression in 3T3-L1 adipocytes. When expressed, SOCS-3 binds to phosphorylated Tyr(960) of the insulin receptor and prevents Stat 5B activation by insulin. Here we show that in COS-7 cells SOCS-3 decreases insulin-induced insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and its association with p85, a regulatory subunit of phosphatidylinositol-3 kinase. This mechanism points to a function of SOCS-3 in insulin resistance. Interestingly, SOCS-3 expression was found to be increased in the adipose tissue of obese mice, but not in the liver and muscle of these animals. Two polypeptides known to be elevated during obesity, insulin and tumor necrosis factor-alpha (TNF-alpha), induce SOCS-3 mRNA expression in mice. Insulin induces a transient expression of SOCS-3 in the liver, muscle, and the white adipose tissue (WAT). Strikingly, TNF-alpha induced a sustained SOCS-3 expression, essentially in the WAT. Moreover, transgenic ob/ob mice lacking both TNF receptors have a pronounced decrease in SOCS-3 expression in the WAT compared with ob/ob mice, providing genetic evidence for a function of this cytokine in obesity-induced SOCS-3 expression. As SOCS-3 appears as a TNF-alpha target gene that is elevated during obesity, and as SOCS-3 antagonizes insulin-induced IRS-1 tyrosine phosphorylation, we suggest that it is a player in the development of insulin resistance.     

Toll-like receptors, inflammation, metabolism and obesity

Obesity is a highly prevalent health problem in Western countries that leads to many important diseases such as type 2 diabetes and metabolic syndrome being now considered an inflammatory chronic disease. Adipocytes are no longer considered passive cells storing fat since they are major producers of inflammatory cytokines during obesity. Adipocytes and macrophages share many biological properties including the synthesis of similar molecules regulating inflammation. Fatty acid levels are elevated in obesity and induce inflammatory pathways by yet a mostly unknown mechanism, leading to the development of insulin and leptin resistance. Recent studies suggest that these effects could be mediated through the activation of toll-like receptors (TLR). TLR signalling pathways might contribute to the development of obesity-associated insulin resistance, thus representing a connection between innate immunity and metabolism. Here, we summarize the recent evidence for the important role that TLRs play in adipose tissue, obesity and insulin resistance.     

GPNMB plays a protective role against obesity-related metabolic disorders by reducing macrophage inflammatory capacity

Obesity is a global health problem that is often related to cardiovascular and metabolic diseases. Chronic low-grade inflammation in white adipose tissue (WAT) is a hallmark of obesity. Previously, during a search for differentially expressed genes in WAT of obese mice, we identified glycoprotein nonmetastatic melanoma protein B (GPNMB), of which expression was robustly induced in pathologically expanded WAT. Here, we investigated the role of GPNMB in obesity-related metabolic disorders utilizing GPNMB-deficient mice. When fed a high-fat diet (HFD), GPNMB-deficient mice showed body weight and adiposity similar to those of wild-type (WT) mice. Nonetheless, insulin and glucose tolerance tests revealed significant obesity-related metabolic disorders in GPNMB-KO mice compared with WT mice fed with HFD. Chronic WAT inflammation was remarkably worsened in HFD-fed GPNMB-KO mice, accompanied by a striking increase in crown-like structures, typical hallmarks for diseased WAT. Macrophages isolated from GPNMB-KO mice were observed to produce more inflammatory cytokines than those of WT mice, a difference abolished by supplementation with recombinant soluble GPNMB extracellular domain. We demonstrated that GPNMB reduced the inflammatory capacity of macrophages by inhibiting NF-κB signaling largely through binding to CD44. Finally, we showed that macrophage depletion by addition of clodronate liposomes abolished the worsened WAT inflammation and abrogated the exacerbation of metabolic disorders in GPNMB-deficient mice fed on HFD. Our data reveal that GPNMB negatively regulates macrophage inflammatory capacities and ameliorates the WAT inflammation in obesity; therefore we conclude that GPNMB is a promising therapeutic target for the treatment of metabolic disorders associated with obesity.     

IL-36 family cytokines in protective versus destructive inflammation

The IL-1 family of cytokines and receptors are critical regulators of inflammation. Within the IL-1 family and in contrast to its IL-1 and IL-18 subfamilies, the IL-36 subfamily is still poorly characterized. Three pro-inflammatory agonists IL-36α, IL-36β, IL-36γ, one IL-36 receptor (IL-1R6) antagonist, IL-36RA, and one putative IL-1R6 antagonist, IL-38, have been grouped into the IL-36 cytokine subfamily. IL-36 agonists signal through a common receptor complex to serve as early triggers of inflammatory responses by activating and cross-regulating a number of inflammatory pathways including NF-κB, MAPK and IFN signaling. IL-36RA binds to IL-1R6 to limit inflammatory signaling, while IL-38 may be an antagonist of more than one IL-1 family receptor. Expression patterns of IL-36 family cytokines, being most prominently expressed in epithelial barrier tissues such as the skin and intestines as well as in immune cells, suggest a role in protecting these barriers from infection. Dysregulation of IL-36 family cytokine signaling at physiological barriers, most prominently the skin, induces autoimmune inflammation. However, transferring the potential of IL-36 to induce tissue damage to tumors might benefit cancer patients. Here we summarize signaling pathways regulated by IL-36 family cytokines, including IL-38, and the consequences for physiological protective and pathophysiological destructive inflammation. Moreover, we discuss the limits of current knowledge on IL-36 family function to open potential avenues for research in the future.     

Overproduction of angiotensinogen from adipose tissue induces adipose inflammation, glucose intolerance, and insulin resistance

Although obesity is associated with overactivation of the white adipose tissue (WAT) renin-angiotensin system (RAS), a causal link between the latter and systemic insulin resistance is not established. We tested the hypothesis that overexpression of angiotensinogen (Agt) from WAT causes systemic insulin resistance via modulation of adipose inflammation. Glucose tolerance, systemic insulin sensitivity, and WAT inflammatory markers were analyzed in mice overexpressing Agt in the WAT (aP2-Agt mice). Proteomic studies and in vitro studies using 3T3-L1 adipocytes were performed to build a mechanistic framework. Male aP2-Agt mice exhibited glucose intolerance, insulin resistance, and lower insulin-stimulated glucose uptake by the skeletal muscle. The difference in glucose tolerance between genotypes was normalized by high-fat (HF) feeding, and was significantly improved by treatment with angiotensin-converting enzyme (ACE) inhibitor captopril. aP2-Agt mice also had higher monocyte chemotactic protein-1 (MCP-1) and lower interleukin-10 (IL-10) in the WAT, indicating adipose inflammation. Proteomic studies in WAT showed that they also had higher monoglyceride lipase (MGL) and glycerol-3-phosphate dehydrogenase levels. Treatment with angiotensin II (Ang II) increased MCP-1 and resistin secretion from adipocytes, which was prevented by cotreating with inhibitors of the nuclear factor-κB (NF-κB) pathway or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, we show for the first time that adipose RAS overactivation causes glucose intolerance and systemic insulin resistance. The mechanisms appear to be via reduced skeletal muscle glucose uptake, at least in part due to Ang II-induced, NADPH oxidase and NFκB-dependent increases in WAT inflammation.     

Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity

Chronic inflammation is an underlying factor linking obesity with insulin resistance. Diet-induced obesity promotes an increase in circulating levels of inflammatory monocytes and their infiltration into expanding adipose tissue. Nevertheless, the endogenous pathways that trigger and sustain chronic low-grade inflammation in obesity are incompletely understood. In this study, we report that a high-fat diet selectively increases the circulating levels of CD11b(+) monocytes in wild-type mice that express leukotriene B(4) receptor, BLT-1, and that this increase is abolished in BLT-1-null mice. The accumulation of classically activated (M1) adipose tissue macrophages (ATMs) and the expression of proinflammatory cytokines and chemokines (i.e., IL-6 and Ccl2) was largely blunted in adipose tissue of obese BLT-1(-/-) mice, whereas the ratio of alternatively activated (M2) ATMs to M1 ATMs was increased. Obese BLT-1(-/-) mice were protected from systemic glucose and insulin intolerance and this was associated with a decrease in inflammation in adipose tissue and liver and a decrease in hepatic triglyceride accumulation. Deletion of BLT-1 prevented high fat-induced loss of insulin signaling in liver and skeletal muscle. These observations elucidate a novel role of chemoattractant receptor, BLT-1, in promoting monocyte trafficking to adipose tissue and promoting chronic inflammation in obesity and could lead to the identification of new therapeutic targets for treating insulin resistance in obesity.     

Expression of TWEAK and its receptor Fn14 in human subcutaneous adipose tissue. Relationship with other inflammatory cytokines in obesity

TWEAK, a cytokine of the TNF family, has been found to be expressed under different inflammatory conditions but no data is available concerning the expression of this cytokine and its receptor (Fn14) in human obesity. In the present work we have evaluated the expression of many pro-inflammatory TNF system cytokines (TNF-alpha, TWEAK and their respective receptors, TNFR1, TNFR2 and Fn14) in human adipose tissue of 84 subjects some with different degree of obesity and type 2 diabetes, and its relation with inflammation by also measuring the expression of macrophage marker CD68. We detected expression of TWEAK and Fn14 in isolated mature adipocytes and in the stromovascular fraction. Additionally, we found that LPS upregulates the expression of both genes on THP-1 human monocytic cell line. TWEAK was expressed in adipose tissue of all studied subjects with no differences between obesity group, and was associated with Fn14 expression in morbid obese, mainly in women with type 2 diabetes. The data obtained here also showed that TNF-alpha and TNFR2 mRNAs were significantly more expressed in subcutaneous adipose tissue of subjects with morbid obesity compared to obese and non-obese subjects. In contrast, TNFR1 gene expression was negatively associated with BMI. Our results suggest that the expression of TNF-derived pro-inflammatory cytokines are increased in severe obesity, where macrophage infiltrate could modulate the inflammatory environment through activation of its receptors.     

FFAs and adipokine-mediated regulation of hsa-miR-143 expression in human adipocytes

Accumulating evidence suggests that microRNAs (miRNAs) play an important role in regulating the pathways in adipose tissue that control processes such as adipogenesis, insulin resistance, and inflammation. MiR-143 is a well-characterized miRNA involved in adipogenesis and may be involved in regulating insulin resistance. Free fatty acids (FFAs) and adipokines, such as tumor necrosis factor-α (TNF-α), leptin, resistin, and interleukin-6 (IL-6), have already been identified as main regulators of obesity and insulin sensitivity. Therefore, we studied the effects of these inflammatory cytokines on the expression of miR-143. FFAs, resistin, and leptin downregulated miR-143 expression in human adipocytes, whereas TNF-α and IL-6 had little effect on miR-143 expression. These results suggest that the expression of miR-143 is affected by a variety of factors that are related to insulin sensitivity. Therefore, miR-143 may be an important mediator in the development of obesity-related insulin resistance.     

Effects of chronic exercise on cytokine production in white adipose tissue and skeletal muscle of rats

White adipose tissue (WAT) is a major source of production of cytokines involved in chronic diseases such as obesity, type 2 diabetes, and atherosclerosis. Long-term exercise has been proposed as a therapy to reduce chronic inflammation. We investigated here the influence of an intense exercise training (over 7 weeks) on several cytokine concentrations including interleukin 1 receptor antagonist (IL-1ra), IL-1beta, and IL-12 in serum, WAT, and skeletal muscle (SM) from non-obese rats. Two groups of 10 rats were investigated: one group was progressively trained (the two last weeks: 120min per day, 25m/min, 7% grade, 5 days per week) and the other age-matched group was used as a sedentary control. Compared to sedentary rats, weight gain was lower in the trained rats (P<0.01). In WAT, concentrations of IL-1ra, IL-1beta, and IL-12 were lower (P<0.001 for IL-1ra and IL-12, P<0.05 for IL-1beta) while they were higher in SM (P<0.01 for IL-1ra, P<0.001 for IL-1beta, P<0.05 for IL-12), and similar in serum. Significant correlations were noted between (i) body weight and WAT concentrations of IL-1ra, IL-1beta, and IL-12 (0.595, 0.450, and 0.481, respectively), (ii) body weight and IL-1beta concentration in SM (-0.526). We also observed significant negative correlations between WAT and SM concentrations of the three cytokines. We show here for the first time that intense exercise training with weight loss reduced concentrations of IL-1ra, IL-1beta, and IL-12 in WAT, while it increased them in SM. These results suggest that exercise could help reduce inflammation in WAT through mobilization of immune cells producing pro- and anti-inflammatory cytokines in SM.     

Inflammatory and prothrombotic states in obese children of European descent

Adipose tissue may release mediators that induce a chronic inflammatory state and alterations in coagulation, which contribute to insulin resistance, atherosclerosis, and thrombosis. We investigated whether inflammatory and/or prothrombotic states exist in obese children and assessed their interrelationship. Sixty-one subjects were recruited, aged between 6 and 16 years, to participate in a cross-sectional study at Children's University Hospital of Geneva. Selected pro/anti-inflammatory cytokines/chemokines and hemostasis parameters were measured in obese children and lean controls. Cardiovascular risk factors in the family were indexed. Fasting glucose level, insulin, prothrombin time (PT), fibrinogen, activated partial thromboplastin time (aPTT), D-dimer, endogenous thrombin potential (ETP), C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-γ-inducible-protein (IP-10), monocyte chemoattractant protein 1 (MCP-1), and interleukin-1 receptor antagonist (IL-1Ra) were measured. We estimated insulin resistance by homeostatic model assessment (HOMA). Anti- (IL-1Ra) and proinflammatory cytokines (MCP-1, IL-6) were significantly increased in obese children in comparison to the control group, even before puberty. Hemostasis was also altered in obese children with a significantly increased fibrinogen level, increased D-dimer, a shortened PT, as well as an increased ETP. No correlation was found between cytokine levels and hemostasis parameters, except for IL-6 and fibrinogen. Obese children present with inflammatory and prothrombotic states as early as 6 years of age and these states are similar in prepubertal and pubertal obese children. The cytokines IL-1Ra and MCP-1 were most significantly increased in obese children. Further investigation is necessary to determine if these cytokines, together with ETP, can reliably predict the development of diabetes and atherosclerosis.     

IRAK1: a critical signaling mediator of innate immunity

The innate immune system is equipped with sensitive and efficient machineries to provide an immediate, first line defense against infections. Toll-like receptors (TLRs) detect pathogens and the IL-1 receptor (IL-1R) family enables cells to quickly respond to inflammatory cytokines by mounting an efficient protective response. Interleukin-1 receptor activated kinases (IRAKs) are key mediators in the signaling pathways of TLRs/IL-1Rs. By means of their kinase and adaptor functions, IRAKs initiate a cascade of signaling events eventually leading to induction of inflammatory target gene expression. Due to this pivotal role, IRAK function is also highly regulated via multiple mechanisms. In this review, we focus on IRAK1, the earliest known and yet the most interesting member of this family. An overview on its structure, function and biology is given, with emphasis on the different novel mechanisms that regulate IRAK1 function. We also highlight several unresolved questions in this field and evaluate the potential of IRAK1 as a target for therapeutic intervention.     

Does obesity play a major role in the pathogenesis of sleep apnoea and its associated manifestations via inflammation, visceral adiposity, and insulin resistance?

Despite the early recognition of the strong association between obstructive sleep apnoea (OSA) and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a "local abnormality" of the respiratory track rather than as a "systemic illness". In 1997, we first reported that the pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNFalpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. In subsequent studies, it was shown that IL-6, TNFalpha, and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat was the primary parameter linked with sleep apnoea. Further studies showed that women with the polycystic ovary syndrome (PCOS) were much more likely than controls to have sleep-disordered breathing (SDB) and daytime sleepiness, suggesting a pathogenetic role of insulin resistance in OSA. Additional accumulated evidence that supports the role of obesity and the associated metabolic aberrations in the pathogenesis of sleep apnoea and related symptoms include: obesity without sleep apnoea is associated with daytime sleepiness; the protective role of gonadal hormones as suggested by the increased prevalence of sleep apnoea in post-menopausal women and the significantly reduced risk for OSA in women on hormonal therapy; partial effects of continuous positive airway pressure (CPAP) in obese patients with apnoea on hypercytokinemia, insulin resistance indices, and visceral fat; and that the prevalence of the metabolic syndrome in the U.S. population from the Third National Health and Nutrition Examination Survey (1988-1994) parallels the prevalence of symptomatic sleep apnoea in general random samples. Furthermore, the beneficial effect of a cytokine antagonist on EDS and apnoea in obese, male apnoeics and that of exercise and weight loss on SDB and EDS in general random or clinical samples, supports the hypothesis that cytokines and insulin resistance are mediators of EDS and sleep apnoea in humans. Finally, our recent finding that in obese, hypothalamic CRH neuron is hypoactive, provides additional evidence on the potential central neural mechanisms for depressed ventilation and consequent development of sleep apnoea in obese individuals. In conclusion, accumulating evidence provides support to our thesis that obesity via inflammation, insulin resistance, visceral adiposity, and central neural mechanisms, e.g. hypofunctioning hypothalamic CRH, play a major role in the pathogenesis of sleep apnoea, sleepiness, and the associated cardiovascular co-morbidities.     

Adipose tissue is a regulated source of interleukin-10

White adipose tissue (WAT) is the source of pro- and anti-inflammatory cytokines and we have recently shown that this tissue is a major source of the anti-inflammatory interleukin (IL)-1 receptor antagonist (IL-1Ra). We now aimed at identifying additional adipose-derived cytokines, which might serve as regulators of IL-1Ra. We demonstrate here for the first time that the antiinflammatory cytokine IL-10 is secreted by human WAT explants and that it is up-regulated by LPS and TNF-alpha in vitro, as well as in obesity in humans (2- and 6-fold increase in subcutaneous and visceral WAT, respectively) and rodents (4-fold increase).