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.
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.
Newborn screening (NBS) for congenital hypothyroidism (CH) was introduced in Switzerland in 1977, which allowed for the preclinical, biochemical diagnosis. The aim of this study was to evaluate the ...prevalence of transient CH (tCH) in the canton of Zurich. In this analytical cohort study, all newborns born in the canton of Zurich, between the 1st of January 2000 and the 30st of June 2016, with a TSH value above 15 mU/L (whole blood) were included. There were 115 cases out of 247,918 babies born during the study period. However, 23 cases had to be excluded due to missing data. The definite diagnosis was made after a thyroxine withdrawal at 2 years of age. The total prevalence of confirmed CH and the female to male ratio (f/m) were 1:2695 and 2.17:1; for permanent CH (pCH), 1:3443 and 2.8:1; and for tCH, 1:12,396 and 1:1, respectively. The TSH value was significantly higher in pCH compared to tCH, at 130.3 (62.9-171.9) and 36.4 (26.5-53.3) (median and interquartile range), respectively (
< 0.001). The prevalences found for congenital hypothyroidism and its transient form are comparable to previous studies. TSH concentration at birth was predictive for the further course of the disease. Low birth weight correlated with a tCH, whereas low gestational age did not. The dominance of the female sex in congenital hypothyroidism is supported by a gender ratio of 2.17:1.
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.
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.
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 libitum- but 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.
The "portal hypothesis" proposes that the liver is directly exposed to free fatty acids and cytokines increasingly released from visceral fat tissue into the portal vein of obese subjects, thus ...rendering visceral fat accumulation particularly hazardous for the development of hepatic insulin resistance and type 2 diabetes. In the present study, we used a fat transplantation paradigm to (artificially) increase intra-abdominal fat mass to test the hypothesis that venous drainage of fat tissue determines its impact on glucose homeostasis.
Epididymal fat pads of C57Bl6/J donor mice were transplanted into littermates, either to the parietal peritoneum (caval/systemic venous drainage) or, by using a novel approach, to the mesenterium, which confers portal venous drainage.
Only mice receiving the portal drained fat transplant developed impaired glucose tolerance and hepatic insulin resistance. mRNA expression of proinflammatory cytokines was increased in both portally and systemically transplanted fat pads. However, portal vein (but not systemic) plasma levels of interleukin (IL)-6 were elevated only in mice receiving a portal fat transplant. Intriguingly, mice receiving portal drained transplants from IL-6 knockout mice showed normal glucose tolerance.
These results demonstrate that the metabolic fate of intra-abdominal fat tissue transplantation is determined by the delivery of inflammatory cytokines to the liver specifically via the portal system, providing direct evidence in support of the portal hypothesis.
Non‐alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and may progress to non‐alcoholic steatohepatitis (NASH) and liver fibrosis. The deficit of pharmacological therapies for ...the latter mainly results from an incomplete understanding of involved pathological mechanisms. Herein, we identify apoptosis signal‐regulating kinase 1 (ASK1) as a suppressor of NASH and fibrosis formation. High‐fat diet‐fed and aged chow‐fed liver‐specific ASK1‐knockout mice develop a higher degree of hepatic steatosis, inflammation, and fibrosis compared to controls. In addition, pharmacological inhibition of ASK1 increased hepatic lipid accumulation in wild‐type mice. In line, liver‐specific ASK1 overexpression protected mice from the development of high‐fat diet‐induced hepatic steatosis and carbon tetrachloride‐induced fibrosis. Mechanistically, ASK1 depletion blunts autophagy, thereby enhancing lipid droplet accumulation and liver fibrosis. In human livers of lean and obese subjects, ASK1 expression correlated negatively with liver fat content and NASH scores, but positively with markers for autophagy. Taken together, ASK1 may be a novel therapeutic target to tackle NAFLD and liver fibrosis.
Synopsis
Liver‐specific ASK1 expression blunts obesity‐associated hepatic steatosis and liver fibrosis potentially through induction of autophagy. Thus, ASK1 may be a novel therapeutic target to tackle NAFLD and liver fibrosis.
Liver‐specific deletion of apoptosis signal‐regulating kinase 1 (ASK1) aggravated high fat diet and age‐induced hepatic steatosis, inflammation and fibrosis in mice.
Liver‐specific ASK1 overexpression protected mice from the development of high fat diet‐induced hepatic steatosis and carbon tetrachloride‐induced fibrosis.
ASK1 depletion blunts autophagy thereby enhancing lipid droplet accumulation.
ASK1 may prevent the development of obesity‐associated hepatic steatosis and liver fibrosis through induction of autophagy.
Liver‐specific ASK1 expression blunts obesity‐associated hepatic steatosis and liver fibrosis potentially through induction of autophagy. Thus, ASK1 may be a novel therapeutic target to tackle NAFLD and liver fibrosis.
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.
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.
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