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ZnT8 is a zinc transporter enriched in pancreatic β-cells, and its polymorphism is associated with increased susceptibility to type 2 diabetes. However, the exact role of ZnT8 in systemic energy metabolism remains elusive. In this study, we found that ZnT8 knockout mice displayed increased adiposity without obvious weight gain. We also observed that the intestinal tract morphology, motility, and gut microbiota were changed in ZnT8 knockout mice. Further study demonstrated that ZnT8 was expressed in enteroendocrine cells, especially in 5-hydroxytryptamine (5-HT)–positive enterochromaffin cells. Lack of ZnT8 resulted in an elevated circulating 5-HT level owing to enhanced expression of tryptophan hydroxylase 1. Blocking 5-HT synthesis in ZnT8-deficient mice restored adiposity, high-fat diet–induced obesity, and glucose intolerance. Moreover, overexpression of human ZnT8 diabetes high-risk allele R325W increased 5-HT levels relative to the low-risk allele in RIN14B cells. Our study revealed an unexpected role of ZnT8 in regulating peripheral 5-HT biogenesis and intestinal microenvironment, which might contribute to the increased risk of obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Sirt6 is an NAD+-dependent deacetylase that is involved in the control of energy metabolism. However, the tissuespecific function of Sirt6 in the adipose tissue remains unknown. In this study, we showed that fat-specific Sirt6 knockout (FKO) sensitized mice to high-fat diet-induced obesity, which was attributed to adipocyte hypertrophy rather than adipocyte hyperplasia. The adipocyte hypertrophy in FKO mice likely resulted from compromised lipolytic activity as an outcome of decreased expression of adipose triglyceride lipase (ATGL), a key lipolytic enzyme. The suppression of ATGL in FKO mice was accounted for by the increased phosphorylation and acetylation of FoxO1, which compromises the transcriptional activity of this positive regulator of ATGL. Fat-specific Sirt6 KO also increased inflammation in the adipose tissue, which may have contributed to insulin resistance in high-fat diet-fed FKO mice. We also observed that in obese patients, the expression of Sirt6 expression is reduced, which is associated with a reduction of ATGL expression. Our results suggest Sirt6 as an attractive therapeutic target for treating obesity and obesity-related metabolic disorders. [ABSTRACT FROM AUTHOR]

The pregnane X receptor (PXR), along with its sister receptor constitutive androstane receptor (CAR), was initially characterized as a xenobiotic receptor that regulates drug metabolism. In this study, we have uncovered an unexpected endobiotic role of PXR in obesity and type 2 diabetes. PXR ablation inhibited high-fat diet (HFD)--induced obesity, hepatic steatosis, and insulin resistance, which were accounted for by increased oxygen consumption, increased mitochondrial b-oxidation, inhibition of hepatic lipogenesis and inflammation, and sensitization of insulin signaling. In an independent model, introducing the allele PXR-/- into the / background also improved body composition and relieved the diabetic phenotype. The / mice deficient of PXR showed increased oxygen consumption and energy expenditure, as well as inhibition of gluconeogenesis and increased rate of glucose disposal during euglycemic clamp. Mechanistically, the metabolic benefits of PXR ablation were associated with the inhibition of c-Jun NH2-terminal kinase activation and downregulation of lipin-1, a novel PXR target gene. The metabolic benefit of PXR ablation was opposite to the reported prodiabetic effect of CAR ablation. Our results may help to establish PXR as a novel therapeutic target, and PXR antagonists may be used for the prevention and treatment of obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Estrogen sulfotransferase (EST), the enzyme responsible for the sulfonation and inactivation of estrogens, plays an important role in estrogen homeostasis. In this study, we showed that induction of hepatic Est is a common feature of type 2 diabetes. Loss of Est in female mice improved metabolic function in ob/ob, dexamethasone-, and high-fat diet--induced mouse models of type 2 diabetes. The metabolic benefit of Est ablation included improved body composition, increased energy expenditure and insulin sensitivity, and decreased hepatic gluconeogenesis and lipogenesis. This metabolic benefit appeared to have resulted from decreased estrogen deprivation and increased estrogenic activity in the liver, whereas such benefit was abolished in ovariectomized mice. Interestingly, the effect of Est was sex-specific, as Est ablation in ob/ob males exacerbated the diabetic phenotype, which was accounted for by the decreased islet β-cell mass and failure of glucose-stimulated insulin secretion in vivo. The loss of β-cell mass in ob/ob males deficient in Est was associated with increased macrophage infiltration and inflammation in white adipose tissue. Our results revealed an essential role of EST in energy metabolism and the pathogenesis of type 2 diabetes. Inhibition of EST, at least in females, may represent a novel approach to manage type 2 diabetes. [ABSTRACT FROM AUTHOR]