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Objective: Induction of browning in white adipose tissue (WAT) increases energy expenditure and may be an attractive target for the treatment of obesity. Since activation of Fas (CD95) induces pathways known to blunt expression of uncoupling protein 1 (UCP1), we hypothesized that Fas expression in adipocytes inhibits WAT browning and thus contributes to the development of obesity., Methods: Adipocyte-specific Fas knockout (Fas Δadipo ) and control littermate (Fas F/F ) mice were fed a regular chow diet or a high-fat diet (HFD) for 20 weeks. Energy expenditure was assessed by indirect calorimetry, and browning was determined in subcutaneous WAT. In vitro, UCP1 was analyzed in subcutaneous murine adipocytes treated with or without Fas ligand. Moreover, FAS expression in WAT was correlated to UCP1 and percentage of body fat in human individuals., Results: HFD-fed Fas Δadipo mice displayed reduced body weight gain and blunted adiposity compared to control littermates. Concomitantly, whole-body energy expenditure and WAT browning were elevated. In cultured adipocytes, Fas ligand treatment blunted isoproterenol-induced UCP1 protein levels. In support of these findings in rodents, FAS expression in WAT correlated negatively with UCP1 but positively with adiposity in human individuals., Conclusions: Fas activation in adipocytes contributes to HFD-associated adiposity in rodents and may be a therapeutic target to reduce obesity and associated diseases., (© 2024 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Interleukin (IL)-6 is a pleotropic cytokine with various physiological and pathophysiological functions in different cells and tissues. In cells residing within white adipose tissue, several, and sometimes conflicting, IL-6 actions have been described in the development of obesity-associated derangements of glucose metabolism. Herein, we aim to summarize opposing findings and discuss recent evidence that IL-6 signaling in adipose tissue is regulated in a depot and cell-specific manner.

We recently demonstrated that removal of one kidney (uninephrectomy [UniNx]) in mice reduced high-fat diet (HFD)-induced adipose tissue inflammation, thereby improving adipose tissue and hepatic insulin sensitivity. Of note, circulating cystatin C (CysC) levels were increased in UniNx compared with sham-operated mice. Importantly, CysC may have anti-inflammatory properties, and circulating CysC levels were reported to positively correlate with obesity in humans and as shown here in HFD-fed mice. However, the causal relationship of such observation remains unclear. HFD feeding of CysC-deficient (CysC knockout [KO]) mice worsened obesity-associated adipose tissue inflammation and dysfunction, as assessed by proinflammatory macrophage accumulation. In addition, mRNA expression of proinflammatory mediators was increased, whereas markers of adipocyte differentiation were decreased. Similar to findings in adipose tissue, expression of proinflammatory cytokines was increased in liver and skeletal muscle of CysC KO mice. In line, HFD-induced hepatic insulin resistance and impairment of glucose tolerance were further aggravated in KO mice. Consistently, chow-fed CysC KO mice were more susceptible to lipopolysaccharide-induced adipose tissue inflammation. In people with obesity, circulating CysC levels correlated negatively with adipose tissue Hif1α as well as IL6 mRNA expression. Moreover, healthy (i.e., insulin-sensitive) subjects with obesity had significantly higher mRNA expression of CysC in white adipose tissue. In conclusion, CysC is upregulated under obesity conditions and thereby counteracts inflammation of peripheral insulin-sensitive tissues and, thus, obesity-associated deterioration of glucose metabolism., (© 2020 by the American Diabetes Association.)

Increasing energy expenditure via induction of adipose tissue browning has become an appealing strategy to treat obesity and associated metabolic complications. Herein, we identify adipocyte-expressed apoptosis signal-regulating kinase 1 (ASK1) as regulator of adipose tissue browning. High fat diet-fed adipocyte-specific ASK1 knockout mice reveal increased UCP1 protein levels in inguinal adipose tissue concomitant with elevated energy expenditure, reduced obesity and ameliorated glucose tolerance compared to control littermates. In addition, ASK1-depletion blunts LPS-mediated downregulation of isoproterenol-induced UCP1 in subcutaneous fat both in vitro and in vivo. Conversely, adipocyte-specific ASK1 overexpression in chow-fed mice attenuates cold-induced UCP1 protein levels in inguinal fat. Mechanistically, ASK1 phosphorylates interferon regulatory factor 3 (IRF3) resulting in reduced Ucp1 expression. Taken together, our studies unravel a role of ASK1 in mediating the inhibitory effect of caloric surplus or LPS-treatment on adipose tissue browning. Adipocyte ASK1 might be a pharmacological target to combat obesity and associated morbidities.

Key Points: A ketogenic diet is known to lead to weight loss and is considered metabolically healthy; however there are conflicting reports on its effect on hepatic insulin sensitivity. KD fed animals appear metabolically healthy in the fasted state after 3 days of dietary challenge, whereas obesogenic high-fat diet (HFD) fed animals show elevated insulin levels. A glucose challenge reveals that both KD and HFD fed animals are glucose intolerant. Glucose intolerance correlates with increased lipid oxidation and lower respiratory exchange ratio (RER); however, all animals respond to glucose injection with an increase in RER. Hyperinsulinaemic-euglycaemic clamps with double tracer show that the effect of KD is a result of hepatic insulin resistance and increased glucose output but not impaired glucose clearance or tissue glucose uptake in other tissues., Abstract: Despite being a relevant healthcare issue and heavily investigated, the aetiology of type 2 diabetes (T2D) is still incompletely understood. It is well established that increased endogenous glucose production (EGP) leads to a progressive increase in glucose levels, causing insulin resistance and eventual loss of glucose homeostasis. The consumption of high carbohydrate, high-fat, western style diet (HFD) is linked to the development of T2D and obesity, whereas the consumption of a low carbohydrate, high-fat, ketogenic diet (KD) is considered healthy. However, several days of carbohydrate restriction are known to cause selective hepatic insulin resistance. In the present study, we compare the effects of short-term HFD and KD feeding on glucose homeostasis in mice. We show that, even though KD fed animals appear to be healthy in the fasted state, they exhibit decreased glucose tolerance to a greater extent than HFD fed animals. Furthermore, we show that this effect originates from blunted suppression of hepatic glucose production by insulin, rather than impaired glucose clearance and tissue glucose uptake. These data suggest that the early effects of HFD consumption on EGP may be part of a normal physiological response to increased lipid intake and oxidation, and that systemic insulin resistance results from the addition of dietary glucose to EGP-derived glucose., (© 2018 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Pro-inflammatory cytokines of a T helper-1-signature are known to promote insulin resistance (IR) in obesity, but the physiological role of this mechanism is unclear. It is also unknown whether and how viral infection induces loss of glycemic control in subjects at risk for developing diabetes mellitus type 2 (DM2). We have found in mice and humans that viral infection caused short-term systemic IR. Virally-induced interferon-γ (IFN-γ) directly targeted skeletal muscle to downregulate the insulin receptor but did not cause loss of glycemic control because of a compensatory increase of insulin production. Hyperinsulinemia enhanced antiviral immunity through direct stimulation of CD8 + effector T cell function. In pre-diabetic mice with hepatic IR caused by diet-induced obesity, infection resulted in loss of glycemic control. Thus, upon pathogen encounter, the immune system transiently reduces insulin sensitivity of skeletal muscle to induce hyperinsulinemia and promote antiviral immunity, which derails to glucose intolerance in pre-diabetic obese subjects. VIDEO ABSTRACT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Obesity variably disrupts human health, but molecular-based patients' health-risk stratification is limited. Adipose tissue (AT) stresses may link obesity with metabolic dysfunction, but how they signal in humans remains poorly-characterized. We hypothesized that a transcriptional AT stress-signaling cascade involving E2F1 and ASK1 (MAP3K5) molecularly defines high-risk obese subtype., Methods: ASK1 expression in human AT biopsies was determined by real-time PCR analysis, and chromatin immunoprecipitation (ChIP) adopted to AT explants was used to evaluate the binding of E2F1 to the ASK1 promoter. Dual luciferase assay was used to measure ASK1 promoter activity in HEK293 cells. Effects of E2F1 knockout/knockdown in adipocytes was assessed utilizing mouse-embryonal-fibroblasts (MEF)-derived adipocyte-like cells from WT and E2F1 -/- mice and by siRNA, respectively. ASK1 depletion in adipocytes was studied in MEF-derived adipocyte-like cells from WT and adipose tissue-specific ASK1 knockout mice (ASK1-ATKO)., Results: Human visceral-AT ASK1 mRNA (N = 436) was associated with parameters of obesity-related cardio-metabolic morbidity. Adjustment for E2F1 expression attenuated the association of ASK1 with fasting glucose, insulin resistance, circulating IL-6, and lipids (triglycerides, HDL-cholesterol), even after adjusting for BMI. Chromatin-immunoprecipitation in human-AT explants revealed BMI-associated increased occupancy of the ASK1 promoter by E2F1 (r 2  = 0.847, p < 0.01). In adipocytes, siRNA-mediated E2F1-knockdown, and MEF-derived adipocytes of E2F1 -knockout mice, demonstrated decreased ASK1 expression and signaling to JNK. Mutation/truncation of an E2F1 binding site in h ASK1 promoter decreased E2F1-induced ASK1 promoter activity, whereas E2F1-mediated sensitization of ASK1 promoter to further activation by TNFα was inhibited by JNK-inhibitor. Finally, MEF-derived adipocytes from adipocyte-specific ASK1 -knockout mice exhibited lower leptin and higher adiponectin expression and secretion, and resistance to the effects of TNFα., Conclusions: AT E2F1 -ASK1 molecularly defines a metabolically-detrimental obese sub-phenotype. Functionally, it may negatively affect AT endocrine function, linking AT stress to whole-body metabolic dysfunction.

Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and are tightly associated with obesity and type 2 diabetes. However, the underlying mechanisms linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. We provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In obese mice, adipocyte-specific gp130 deletion reduced basal lipolysis and enhanced insulin's ability to suppress lipolysis from mesenteric but not epididymal adipocytes. Consistently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Of note, adipocyte-specific gp130 knockout mice were protected from high-fat diet-induced hepatic steatosis as well as from insulin resistance. In humans, omental but not subcutaneous IL-6 mRNA expression correlated positively with liver lipid accumulation (r = 0.31, P < 0.05) and negatively with hyperinsulinemic-euglycemic clamp glucose infusion rate (r = -0.28, P < 0.05). The results show that IL-6 cytokine-induced lipolysis may be restricted to mesenteric white adipose tissue and that it contributes to hepatic insulin resistance and steatosis. Therefore, blocking IL-6 cytokine signaling in (mesenteric) adipocytes may be a novel approach to blunting detrimental fat-liver crosstalk in obesity., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Reduced kidney mass and/or function may result in multiple metabolic derangements, including insulin resistance. However, underlying mechanisms are poorly understood. Herein, we aimed to determine the impact of reduced kidney mass on glucose metabolism in lean and obese mice. To that end, 7-week-old C57BL/6J mice underwent uninephrectomy (UniNx) or sham operation. After surgery, animals were fed either a chow (standard) diet or a high-fat diet (HFD), and glucose homeostasis was assessed 20 weeks after surgery. Intraperitoneal glucose tolerance was similar in sham-operated and UniNx mice. However, insulin-stimulated glucose disposal in vivo was significantly diminished in UniNx mice, whereas insulin-stimulated glucose uptake into isolated skeletal muscle was similar in sham-operated and UniNx mice. Of note, capillary density was significantly reduced in skeletal muscle of HFD-fed UniNx mice. In contrast, hepatic insulin sensitivity was improved in UniNx mice. Furthermore, adipose tissue hypoxia-inducible factor 1α expression and inflammation were reduced in HFD-fed UniNx mice. Treatment with the angiotensin II receptor blocker telmisartan improved glucose tolerance and hepatic insulin sensitivity in HFD-fed sham-operated but not UniNx mice. In conclusion, UniNx protects from obesity-induced adipose tissue inflammation and hepatic insulin resistance, but it reduces muscle capillary density and, thus, deteriorates HFD-induced skeletal muscle glucose disposal., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Obesity has been reported as an independent risk factor for chronic kidney disease, leading to glomerulosclerosis and renal insufficiency. To assess the relationship between a reduced nephron number and a particular susceptibility to obesity-induced renal damage, mice underwent uninephrectomy (UNX) followed by either normal chow or high-fat diet (HFD) and were compared with sham-operated control mice. After 20 weeks of dietary intervention, HFD-fed control mice presented characteristic features of progressive nephropathy, including albuminuria, glomerulosclerosis, renal fibrosis and oxidative stress. These changes were more pronounced in HFD-fed mice that had undergone uninephrectomy. Analysis of gene expression in mouse kidney by whole genome microarrays indicated that high fat diet led to more changes in gene expression than uninephrectomy. HFD affected mainly genes involved in lipid metabolism and transport, whereas the combination of UNX and HFD additionally altered the expression of genes belonging to cytoskeleton remodeling, fibrosis and hypoxia pathways. Canonical pathway analyses identified the farnesoid X receptor (FXR) as a potential key mediator for the observed changes in gene expression associated with UNX-HFD. In conclusion, HFD-induced kidney damage is more pronounced following uninephrectomy and is associated with changes in gene expression that implicate FXR as a central regulatory pathway., (Copyright © 2014. Published by Elsevier B.V.)

Obesity is associated with altered gut microbiota composition and impaired gut barrier function. These changes, together with interrelated mesenteric adipose tissue inflammation, result in increased release of pro-inflammatory cytokines, bacteria-derived factors, and lipids into the portal circulation, promoting the development of (hepatic) insulin resistance. Herein, the potential impact of obesity-related changes in gut and visceral adipose tissue biology on the development of insulin resistance and Type 2 diabetes is reviewed., (©2014 Int. Union Physiol. Sci./Am. Physiol. Soc.)

Low-grade inflammation in adipose tissue and liver has been implicated in obesity-associated insulin resistance and type 2 diabetes. Yet, the contribution of inflammatory cells to the pathogenesis of skeletal muscle insulin resistance remains elusive. In a large cohort of obese human individuals, blood monocyte Fas (CD95) expression correlated with systemic and skeletal muscle insulin resistance. To test a causal role for myeloid cell Fas expression in the development of skeletal muscle insulin resistance, we generated myeloid/haematopoietic cell-specific Fas-depleted mice. Myeloid/haematopoietic Fas deficiency prevented the development of glucose intolerance in high fat-fed mice, in ob/ob mice, and in mice acutely challenged by LPS. In vivo, ex vivo and in vitro studies demonstrated preservation of muscle insulin responsiveness with no effect on adipose tissue or liver. Studies using neutralizing antibodies demonstrated a role for TNFα as mediator between myeloid Fas and skeletal muscle insulin resistance, supported by significant correlations between monocyte Fas expression and circulating TNFα in humans. In conclusion, our results demonstrate an unanticipated crosstalk between myeloid cells and skeletal muscle in the development of obesity-associated insulin resistance.

Context: Deletion of the death receptor Fas (CD95) in adipocytes of mice is associated with improved insulin sensitivity and reduced adipose tissue (AT) inflammation., Objective: Here we investigate the relationship of AT Fas with human obesity., Design and Methods: In paired samples of omental and sc AT from 256 lean and obese (including insulin-sensitive and insulin-resistant subgroups; n=60) participants, we investigated whether Fas and Fas-ligand (FasL) mRNA expression is fat depot-specific, altered in obesity, and related to measures of AT inflammation and insulin sensitivity. In addition, AT Fas mRNA expression was measured in 16 obese patients after significant weight loss of 45±6.3 kg in the context of a two-step bariatric surgery strategy., Results: Fas and FasL are significantly higher expressed in omental (OM) compared to sc AT. Fas expression correlates with body mass index (OM, r2=0.44; sc, r2=0.14), AT macrophage infiltration (OM, r2=0.36; sc, r2=0.16), and glucose infusion rate in euglycemic-hyperinsulinemic clamps (OM, r2=0.17; sc, r2=0.13) (P<.05 for all). FasL expression most strongly correlates with adipocyte size (OM, r2=0.32; sc, r2=0.17) and AT macrophage infiltration (OM, r2=0.46; sc, r2=0.02). Insulin-sensitive obese individuals had significantly lower Fas and FasL expression than insulin-resistant obese individuals. Significant weight loss 12 months after gastric sleeve resection is associated with a significantly reduced Fas expression in OM and sc fat depots., Conclusions: Independently of body weight, increased Fas expression may contribute to impaired insulin sensitivity and AT dysfunction in obesity. Moreover, significant weight loss reduces Fas expression in OM and sc fat depots.

The inflammasome has been recently implicated in obesity-associated dys-metabolism. However, of its products, the specific role of IL-1β was clinically demonstrated to mediate only the pancreatic beta-cell demise, and in mice mainly the intra-hepatic manifestations of obesity. Yet, it remains largely unknown if IL-1β, a cytokine believed to mainly function locally, could regulate dysfunctional inter-organ crosstalk in obesity. Here we show that High-fat-fed (HFF) mice exhibited a preferential increase of IL-1β in portal compared to systemic blood. Moreover, portally-drained mesenteric fat transplantation from IL-1βKO donors resulted in lower pyruvate-glucose flux compared to mice receiving wild-type (WT) transplant. These results raised a putative endocrine function for visceral fat-derived IL-1β in regulating hepatic gluconeogenic flux. IL-1βKO mice on HFF exhibited only a minor or no increase in adipose expression of pro-inflammatory genes (including macrophage M1 markers), Mac2-positive crown-like structures and CD11b-F4/80-double-positive macrophages, all of which were markedly increased in WT-HFF mice. Further consistent with autocrine/paracrine functions of IL-1β within adipose tissue, adipose tissue macrophage lipid content was increased in WT-HFF mice, but significantly less in IL-1βKO mice. Ex-vivo, adipose explants co-cultured with primary hepatocytes from WT or IL-1-receptor (IL-1RI)-KO mice suggested only a minor direct effect of adipose-derived IL-1β on hepatocyte insulin resistance. Importantly, although IL-1βKOs gained weight similarly to WT-HFF, they had larger fat depots with similar degree of adipocyte hypertrophy. Furthermore, adipogenesis genes and markers (pparg, cepba, fabp4, glut4) that were decreased by HFF in WT, were paradoxically elevated in IL-1βKO-HFF mice. These local alterations in adipose tissue inflammation and expansion correlated with a lower liver size, less hepatic steatosis, and preserved insulin sensitivity. Collectively, we demonstrate that by promoting adipose inflammation and limiting fat tissue expandability, IL-1β supports ectopic fat accumulation in hepatocytes and adipose-tissue macrophages, contributing to impaired fat-liver crosstalk in nutritional obesity.

Adipose tissue inflammation is linked to the pathogenesis of insulin resistance. In addition to exerting death-promoting effects, the death receptor Fas (also known as CD95) can activate inflammatory pathways in several cell lines and tissues, although little is known about the metabolic consequence of Fas activation in adipose tissue. We therefore sought to investigate the contribution of Fas in adipocytes to obesity-associated metabolic dysregulation. Fas expression was markedly increased in the adipocytes of common genetic and diet-induced mouse models of obesity and insulin resistance, as well as in the adipose tissue of obese and type 2 diabetic patients. Mice with Fas deficiency either in all cells or specifically in adipocytes (the latter are referred to herein as AFasKO mice) were protected from deterioration of glucose homeostasis induced by high-fat diet (HFD). Adipocytes in AFasKO mice were more insulin sensitive than those in wild-type mice, and mRNA levels of proinflammatory factors were reduced in white adipose tissue. Moreover, AFasKO mice were protected against hepatic steatosis and were more insulin sensitive, both at the whole-body level and in the liver. Thus, Fas in adipocytes contributes to adipose tissue inflammation, hepatic steatosis, and insulin resistance induced by obesity and may constitute a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.

The cytokine interleukin (IL)-27 has been reported to induce thermogenesis in white adipocytes. However, it remains unknown whether IL-27-mediated adipocyte energy dissipation is paralleled by an elevated energy supply from lipids and/or carbohydrates. We hypothesized that IL-27 increases lipolysis and glucose uptake in white adipocytes, thereby providing substrates for thermogenesis. Unexpectedly, we found that treatment of 3T3-L1 adipocytes with IL-27 reduced intra- and extracellular free fatty acid (FFA) concentrations and that phosphorylation of hormone-sensitive lipase (HSL) was not affected by IL-27. These results were confirmed in subcutaneous white adipocytes. Further, application of IL-27 to 3T3-L1 adipocytes increased intracellular triglyceride (TG) content but not mitochondrial ATP production nor expression of enzymes involved in beta-oxidation indicating that elevated esterification rather than oxidation causes FFA disappearance. In addition, IL-27 significantly increased GLUT1 protein levels, basal glucose uptake as well as glycolytic ATP production, suggesting that increased glycolytic flux due to IL-27 provides the glycerol backbone for TG synthesis. In conclusion, our findings suggest IL-27 increases glucose uptake and TG deposition in white adipocytes. [ABSTRACT FROM AUTHOR]

Increasing energy expenditure via induction of browning in white adipose tissue has emerged as a potential strategy to treat obesity and associated metabolic complications. We previously reported that ASK1 inhibition in adipocytes protected from high-fat diet (HFD) or lipopolysaccharide (LPS)-mediated downregulation of UCP1 both in vitro and in vivo. Conversely, adipocyte-specific ASK1 overexpression attenuated cold-induction of UCP-1 in inguinal fat. Herein, we provide evidence that both TNFα-mediated and HFD-induced activation of p38 MAPK in white adipocytes are ASK1-dependent. Moreover, expression of senescence markers was reduced in HFD-fed adipocyte-specific ASK1 knockout mice. Similarly, LPS-induced upregulation of senescence markers was blunted in ASK1-depleted adipocytes. Thus, our study identifies a previously unknown role for ASK1 in the induction of stress-induced senescence. [ABSTRACT FROM AUTHOR]

Four days of high-fat diet (HFD) feeding are sufficient to induce glucose intolerance and hepatic steatosis in mice. While prolonged HFD-induced metabolic complications are partly mediated by increased food intake during the light (inactive) phase, such a link has not yet been established in short-term HFD-fed mice. Herein, we hypothesized that a short bout of HFD desynchronizes feeding behavior, thereby contributing to glucose intolerance and hepatic steatosis. To this end, 12-wk-old C57BL/6J littermates were fed a HFD for 4 days either ad libitum or intermittently. Intermittent-fed mice were fasted for 8 h during their inactive phase. Initiation of HFD led to an immediate increase in food intake already during the first light phase. Moreover, glucose tolerance was significantly impaired in ad libitumbut not in intermittent HFD-fed mice, indicating that desynchronized feeding behavior contributes to short-term HFD-induced glucose intolerance. Of note, overall food intake was similar between the groups, as was body weight. However, intermittent HFD-fed mice revealed higher fat depot weights. Phosphorylation of hormone sensitivity lipase and free fatty acid release from isolated adipocytes were significantly elevated, suggesting increased lipolysis in intermittent HFD-fed mice. Moreover, hepatic mRNA expression of lipogenetic enzymes and liver triglyceride levels were significantly increased in intermittent HFD-fed mice. Importantly, food deprivation decreased respiratory exchange ratio promptly in intermittent- but not in ad libitum HFD-fed mice. In conclusion, retaining a normal feeding pattern prevented HFD-induced impairment of metabolic flexibility in short-term HFD-fed mice. [ABSTRACT FROM AUTHOR]

High secretion of interleukin (IL)-6 from white adipose tissue may contribute to metabolic complications in obesity. We have recently shown that IL-6-type cytokine signaling in adipocytes is involved in the development of obesity-associated hepatic insulin resistance and steatosis. In addition, we revealed that adipocyte-specific IL-6 signaling ameliorates glucose metabolism in obesity via enhancing insulin secretion. Mechanistically, IL-6 induces the release of free fatty acid (FFA) and leptin from adipocytes thereby affecting liver metabolism and pancreatic β-cell function, respectively. This commentary further discusses the role of adipocyte-specific IL-6-type cytokine signaling in the regulation of FFA and leptin release. In particular, we outline depot-specific differences in IL-6-induced basal release of the two aforementioned factors. Moreover, we provide evidence that insulin’s effect on the release of FFA and leptin is adipose depot-dependent. We conclude that adipose depot-specific targeting of the IL-6 signaling pathway may be a novel approach to blunt obesity-associated metabolic complications. [ABSTRACT FROM AUTHOR]

In established obesity, inflammation and macrophage recruitment likely contribute to the development of insulin resistance. In the current study, we set out to explore whether adipose tissue infiltration by neutrophils that occurs early (3 days) after initiating a high-fat diet (HFD) could contribute to the early occurrence of hepatic insulin resistance and to determine the role of cytosolic phospholipase A2α (cPLA2α) in this process. The 3-day HFD caused a significant upregulation of cPLA2α in periepididymal fat and in the liver. A specific antisense oligonucleotide (AS) effectively prevented cPLA2α induction, neutrophil infiltration into adipose tissue (likely involving MIP-2), and protected against 3-day HFD--induced impairment in hepatic insulin signaling and glucose over-production from pyruvate. To sort out the role of adipose neutrophil infiltration independent of cPLA2α induction in the liver, mice were injected intraperitoneally with anti--intracellular adhesion molecule-1 (ICAM-1) antibodies. This effectively prevented neutrophil infiltration without affecting cPLA2α or MIP-2, but like AS, prevented impairment in hepatic insulin signaling, the enhanced pyruvate-to-glucose flux, and the impaired insulin-mediated suppression of hepatic glucose production (assessed by clamp), which were induced by the 3-day HFD. Adipose tissue secretion of tumor necrosis factor-α (TNF-α) was increased by the 3-day HFD, but not if mice were treated with AS or ICAM-1 antibodies. Moreover, systemic TNF-α neutralization prevented 3-day HFD--induced hepatic insulin resistance, suggesting its mediatory role. We propose that an acute, cPLA2α-dependent, neutrophil-dominated inflammatory response of adipose tissue contributes to hepatic insulin resistance and glucose overproduction in the early adaptation to high-fat feeding. [ABSTRACT FROM AUTHOR]

Given the strong link between visceral adiposity and (hepatic) insulin resistance as well as liver steatosis, it is crucial to characterize obesity-associated alterations in adipocyte function, particularly in fat depots drained to the liver. Yet these adipose tissues are not easily accessible in humans, and the most frequently studied depot in rodents is the perigonadal, which is drained systemically. In the present study, we aimed to study alterations in lipolysis between mesenteric and perigonadal adipocytes in mice. Basal free fatty acid and glycerol release was significantly lower in perigonadal compared with mesenteric adipocytes isolated from chow-fed C57BL/6J mice. However, this difference completely vanished in high-fat diet-fed mice. Consistently, protein levels of the G0/G1 switch gene 2 (G0S2), which were previously found to be inversely related to basal lipolysis, were significantly lower in mesenteric compared with perigonadal fat of chow-fed mice. Similarly, perilipin was differently expressed between the two depots. In addition, adipocyte-specific overexpression of G0S2 led to significantly decreased basal lipolysis in mesenteric adipose tissue of chow-fed mice. In conclusion, lipolysis is differently regulated between perigonadal and mesenteric adipocytes, and these depot-specific differences might be explained by altered regulation of G0S2 and/or perilipin. [ABSTRACT FROM AUTHOR]

Exercise, obesity and type 2 diabetes are associated with elevated plasma concentrations of interleukin-6 (IL-6). Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion. Here we show that administration of IL-6 or elevated IL-6 concentrations in response to exercise stimulate GLP-1 secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by GCG) and prohormone convertase 1/3 expression. In models of type 2 diabetes, the beneficial effects of IL-6 were maintained, and IL-6 neutralization resulted in further elevation of glycemia and reduced pancreatic GLP-1. Hence, IL-6 mediates crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand. This previously unidentified endocrine loop implicates IL-6 in the regulation of insulin secretion and suggests that drugs modulating this loop may be useful in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state. Protein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130Δadipo) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modeled in vitro by exposing mature adipocytes to isoproterenol after stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively. Inguinal WAT of HFD-fed gp130Δadipo mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro , treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. As with mouse data, OSM gene expression in human WAT positively correlated with BMI (r = 0.284, p = 0.021, n = 66) and negatively with UCP1 expression (r = −0.413, p < 0.001, n = 66). Our data support the notion that OSM negatively regulates thermogenesis in WAT and thus may be an attractive target for treating obesity. [Display omitted] • OSM is regulated under obesity and negatively correlates with UCP1 in WAT. • OSM suppresses isoproterenol-induced UCP1 in subcutaneous adipocytes. • OSM signals through the gp130-STAT3 pathway to lower UCP1 expression. • Obese mice lacking gp130 in adipocytes exhibit increased WAT browning. [ABSTRACT FROM AUTHOR]