Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic tumour-necrosis factor (TNF)-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders.

Metformin treatment of rats at physiologically relevant doses inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase. Metformin, possibly the most widely prescribed antidiabetic in the world, specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia. Its molecular mechanism of action remains elusive and is of great interest. This study shows that metformin treatment of rats at physiologically relevant doses inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase (mGPD), which modulates the cytosolic and mitochondrial redox state, resulting in a reduction in endogenous glucose production. These results identify mGPD as one of the molecular targets by which guanides and biguanides inhibit hepatic gluconeogenesis, and provide a novel therapeutic avenue for type 2 diabetes. Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia1,2. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. Here we show that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Acute and chronic low-dose metformin treatment effectively reduced endogenous glucose production, while increasing cytosolic redox and decreasing mitochondrial redox states. Antisense oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats resulted in a phenotype akin to chronic metformin treatment, and abrogated metformin-mediated increases in cytosolic redox state, decreases in plasma glucose concentrations, and inhibition of endogenous glucose production. These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice. These results have significant implications for understanding the mechanism of metformin’s blood glucose lowering effects and provide a new therapeutic target for type 2 diabetes.

Calcium cycling induced by the SERCA2b–RyR2 pathway in beige fat cells allows for thermogenic activity independent of UCP1. Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b–RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca2+ cycling.

Obesity is associated with a chronic state of low-grade inflammation and progressive tissue infiltration by immune cells and increased expression of inflammatory cytokines. It is established that interleukin 6 (IL6) regulates multiple aspects of metabolism, including glucose disposal, lipolysis, oxidative metabolism, and energy expenditure. IL6 is secreted by many tissues, but the role of individual cell types is unclear. We tested the role of specific cells using a mouse model with conditional expression of the Il6 gene. We found that IL6 derived from adipocytes increased, while IL6 derived from myeloid cells and muscle suppressed, macrophage infiltration of adipose tissue. These opposite actions were associated with a switch of IL6 signaling from a canonical mode (myeloid cells) to a noncanonical trans-signaling mode (adipocytes and muscle) with increased expression of the ADAM10/17 metalloprotease that promotes trans-signaling by the soluble IL6 receptor α. Collectively, these data demonstrate that the source of IL6 production plays a major role in the physiological regulation of metabolism. Significance Chronic low-grade inflammation is a key driver of metabolic syndrome. This inflammatory response is mediated by immune-cell infiltration and the expression of inflammatory cytokines. IL6 is implicated in this response, but the physiological role of IL6 signaling is unclear. Here, we demonstrate that the source of IL6 influences the nature of the inflammatory response. We report that IL6 secreted by myeloid cells inhibits adipose tissue macrophage (ATM) accumulation by a canonical signaling mechanism, but IL6 secreted by adipocytes or muscle promotes ATM accumulation by a noncanonical mechanism. These observations provide physiological insight into the complexity of IL6-mediated regulation of inflammation.

Zipping up obesity: Chylomicrons are specialized particles that carry dietary fats from the intestine to the bloodstream for absorption into the body. Lacteals are lymphatic vessels that act as the highway for chylomicron transport, but it is unclear how passage occurs. Zhang et al. report that two endothelial cell receptors, neuropilin-1 (NRP1) and vascular endothelial growth factor receptor 1 (VEGFR1, also known as FLT1), are required to convert the entry spaces between lacteals from open junctions to closed, zipped structures (see the Perspective by McDonald). Mice that were fed a high-fat diet were subsequently rendered resistant to weight gain if NRP1 and FLT1 were inactivated. Science , this issue p. 599 ; see also p. 551