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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. Understanding the regulatory mechanisms governing brown and beige adipose mediated thermogenesis is of interest in order to develop therapeutic strategies to treat obesity. Here, the authors show that adipocyte-expressed apoptosis signal-regulating kinase 1 (ASK1) inhibits browning in response to cold, β3 receptor activation, and LPS.

Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia. How heavy a person is and how much active brown fat they have depends on their father and the season in which they were conceived.

Chitin-glucan (CG) represents a natural carbohydrate source for certain microbial inhabitants of the human gut and may act as a prebiotic for a number of bacterial taxa. However, the bifidogenic activity of this substrate is still unknown. In the current study, we evaluated the ability of chitin-glucan to influence growth of 100 bifidobacterial strains belonging to those species commonly identified within the bifidobacterial communities residing in the infant and adult human gut. Such analyses were coupled with transcriptome experiments directed to explore the transcriptional effects of CG on Bifidobacterium breve 2L, which was shown to elicit the highest growth performance on this natural polysaccharide. In addition, an in vivo trial involving a rat model revealed how the colonization efficiency of this bifidobacterial strain was enhanced when the animals were fed with a diet containing CG. Altogether our analyses indicate that CG is a valuable novel prebiotic compound that may be added to the human diet in order to re-establish/reinforce bifidobacteria colonization in the mammalian gut.

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. Graphical Abstract 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.

Aims/hypothesisIn the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy.MethodsWe studied the role of antioxidants in the regulation of insulin resistance using the tamoxifen-inducible fat-specific insulin receptor knockout (iFIRKO) mouse model, which allowed us to analyse the antioxidant’s effect in a time-resolved manner. In addition, leptin-deficient ob/ob mice were used as a hyperphagic, chronically obese and diabetic mouse model to validate the beneficial effect of antioxidants on metabolism.ResultsAcute induction of insulin receptor knockout in adipocytes changed the substrate preference to fat before induction of a diabetic phenotype including hyperinsulinaemia and hyperglycaemia. In healthy chow-fed animals as well as in morbidly obese mice, this diabetic phase could be reversed within a few weeks. Furthermore, after the induction of insulin receptor knockout in mature adipocytes, iFIRKO mice were protected from subsequent obesity development through high-fat diet feeding. By genetic tracing we show that the persistent fat mass loss in mice after insulin receptor knockout in adipocytes is not caused by the depletion of adipocytes. Treatment of iFIRKO mice with antioxidants postponed and reduced hyperglycaemia by increasing insulin sensitivity. In ob/ob mice, antioxidants rescued both hyperglycaemia and hyperphagia.Conclusions/interpretationWe conclude that fat mass reduction through insulin resistance in adipocytes is not reversible. Furthermore, it seems unlikely that adipocytes undergo apoptosis during the process of extreme lipolysis, as a consequence of insulin resistance. Antioxidants have a beneficial health effect not only during the acute phase of diabetes development, but also in a temporary fashion once chronic obesity and diabetes have been established.

MicroRNAs (miRNAs) are key regulators of cellular processes, including mitochondrial function and energy metabolism. This study explores the regulation of miR‐494 in skeletal muscle and circulation, investigating its response to exercise training and an acute exercise bout, its association with metabolic disorders, and the effects of electrical pulse stimulation (EPS). In addition, it validates the gene targets and physiological role of miR‐494 using gain‐ and loss‐of‐function studies in primary human skeletal muscle cells. We demonstrate that miR‐494 levels in both skeletal muscle and circulation are influenced by long‐term exercise training, which induces adaptive changes, but remain unaffected by an acute bout of exercise. EPS does not alter miR‐494 levels in cultured primary human skeletal muscle cells. Moreover, muscle miR‐494 levels remain unchanged under various metabolic challenges, including obesity and type 2 diabetes. Genetic manipulation of miR‐494 in primary human skeletal muscle cells modulates mitochondrial biogenesis and function, as well as lipid metabolism, through targeting PGC1A and SIRT1 . Injection of a miR‐494 inhibitor into skeletal muscle of mice supports the role of miR‐494 in regulating Pgc1α mRNA, suggesting potential therapeutic implications. These findings highlight miR‐494 as a significant modulator of mitochondrial dynamics and energy metabolism in skeletal muscle. What is the central question of this study? How is miR‐494 regulated in skeletal muscle and circulation and what are its responses to exercise training and an acute exercise bout, its association with metabolic disorders, and the effects of electrical pulse stimulation? What is the main finding and its importance? miR‐494 is downregulated in trained muscle but not affected by acute exercise and the presence of metabolic disease. Inhibition of miR‐494 promotes mitochondrial biogenesis and respiration in primary human skeletal muscle cells through upregulation of PGC1A and SIRT1. These results highlight miR‐494 as a significant modulator of mitochondrial dynamics and energy metabolism.

The human gut microbiota has been linked to the health status of the host. Modulation of human gut microbiota through pro- and prebiotic interventions has yielded promising results; however, the effect of novel prebiotics, such as chitin–glucan, on gut microbiota–host interplay is still not fully characterized. We assessed the effect of chitin–glucan (CG) and chitin–glucan plus Bifidobacterium breve (CGB) on human gut microbiota from the luminal and mucosal environments in vitro. Further, we tested the effect of filter-sterilized fecal supernatants from CG and CGB fermentation for protective effects on inflammation-induced barrier disruption and cytokine production using a co-culture of enterocytes and macrophage-like cells. Overall, CG and CGB promote health-beneficial short-chain fatty acid production and shift human gut microbiota composition, with a consistent effect increasing Roseburia spp. and butyrate producing-bacteria. In two of three donors, CG and CGB also stimulated Faecalibacterium prausniitzi. Specific colonization of B. breve was observed in the lumen and mucosal compartment; however, no synergy was detected for different endpoints when comparing CGB and CG. Both treatments included a significant improvement of inflammation-disrupted epithelial barrier and shifts on cytokine production, especially by consistent increase in the immunomodulatory cytokines IL10 and IL6.

A creatine futile cycle has been shown to contribute to energy expenditure in beige adipocytes in preclinical mouse models of obesity. In this issue of Nature Metabolism , Connell and colleagues show that creatine supplementation in healthy young female vegetarians unfortunately affects neither human brown adipocyte activity nor cold-induced energy expenditure.

IntroductionIrritable bowel syndrome (IBS) is a prevalent and challenging condition with limited therapeutic options. In order to assess the potential of CG as an alternative for IBS management, we performed an array of preclinical studies to evaluate the roles of Chitin-Glucan (CG), a safe dietary prebiotic, on the IBS physiopathological mechanisms, such as visceral analgesia, intestinal inflammation, barrier function.MethodsVisceral pain was recorded in a rat model with colon hypersensitivity induced by TNBS. Intracolonic pressure was assessed in animals receiving CG at a human equivalent dose (HED) of 1.5 g/d or 3 g/d and compared to negative- (tap water) and positive- (phloroglucinol) control groups. The anti-inflammatory effect of CG was evaluated using clinical and histological scores in DSS-induced mice. HT-29 cells were treated with CG to evaluate changes related to analgesia, inflammation and barrier. Molecular modelling explored the ability of CG to chelate microbial pathogenic lipids.ResultsOral administration of CG in rats or mice was well tolerated without diarrhea or inflammation evaluated at histologic and molecular levels. CG at 3 g/d HED significantly decreased visceral perception by 14% after 2 weeks (p<0.01) and reduced inflammation by 50% promoting mucosal regeneration in DSS-induced colitis mice. CG at 1.5 g/d HED reduced visceral pain perception by 20% in TNBS-colitis induced rats with CG at 1.5 g/d HED after 5 weeks (p<0.01). At 3 g/d HED, this analgesic effect was superior to phloroglucinol with a faster onset of action and a 50% inhibition of pain perception (p<0.0001). The molecular mechanisms of CG involved at least in part a significant induction of MOR, CB2 receptor, IL-10 and a significant decrease of pro-inflammatory cytokines IL-1β and IL-8 mRNA. CG also significantly up-regulated barrier-related genes like muc5AC, claudin-2 and ZO-2. CG molecular modelling revealed a new property of the molecule as a chelator of microbial pathogenic lipids.ConclusionCG decreased visceral perception and intestinal inflammation through master genes regulation and direct binding of microbial products, giving evidence-based CG as a promising treatment for patients with IBS or IBS-like symptoms.

The perception of adipose tissue, both in the scientific community and in the general population, has changed dramatically in the past 20 years. While adipose tissue was thought for a long time to be a rather simple lipid storage entity, it is now recognized as a highly heterogeneous organ and a critical regulator of systemic metabolism, composed of many different subtypes of cells, with important endocrine functions. Additionally, adipose tissue is nowadays recognized to contribute to energy turnover, due to the presence of specialized thermogenic adipocytes, which can be found in many adipose depots. This review discusses the unprecedented insights that we have gained into the heterogeneity of thermogenic adipocytes and their respective precursors due to the technical developments in single-cell and nucleus technologies. These methodological advances have increased our understanding of how adipose tissue catabolic function is influenced by developmental and intercellular communication events. Adipose tissue has emerged as a highly heterogeneous organ. Sun et al. discuss the heterogeneity of thermogenic adipocytes and their precursors, highlighting the single-cell technologies that help to characterize adipose tissues in depth.