Sirt6 is an NAD-dependent deacetylase that is involved in the control of energy metabolism. However, the tissue-specific 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.

Sirt6 is one of the sirtuin family members, a kind of NAD+-dependent histone deacetylase and ADP-ribose transferase enzyme. It has an important role in physiological and pathological processes, regulating aging, cancer, obesity, insulin resistance, inflammation, and energy metabolism. Recent studies have suggested that reduced Sirt6 action is related to obesity and diabetes. Aging and overnutrition, two major risk factors for obesity and diabetes, lead to decreased Sirt6 level and function, which results in abnormal glucose and lipid metabolism. Whole-body ablation of Sirt6 in mice results in severe hypoglycemia. Sirt6 deficiency leads to liver steatosis and promotes diet-induced obesity and insulin resistance. Sirt6 has a protective effect on obesity and diabetes. This review surveys evidence for an emerging role of Sirt6 as a regulator of metabolism in mammals and summarizes its major functions in obesity and diabetes.

Irisin, a hormone proteolytically processed from fibronectin type III domain-containing protein 5 (FNDC5), has been reported to induce the browning of sc adipocytes by increasing the level of uncoupling protein 1. In this study, we showed that activation of the nuclear receptor constitutive androstane receptor induced FNDC5 mRNA expression in the liver and increased the circulating level of irisin in mice. FNDC5/irisin is a direct transcriptional target of constitutive androstane receptor. Hepatic-released irisin functioned as a paracrine/autocrine factor that inhibited lipogenesis and gluconeogenesis via the Adenosine 5'-monophosphate (AMP)-activated protein kinase pathway. Adenovirus-overexpressed irisin improved hepatic steatosis and insulin resistance in genetic-induced obese mice. Irisin transgenic mice were also protected against high-fat diet-induced obesity and insulin resistance. In conclusion, our results reveal a novel pathway in regulating FNDC5/irisin expression and identify a physiological role for this hepatic hormone in glucose and lipid homeostasis.

Activating beige adipocytes in white adipose tissue (WAT) to increase energy expenditure is a promising strategy to combat obesity. We identified that mesencephalic astrocyte–derived neurotrophic factor (Manf) is a feeding-induced hepatokine. Liver-specific Manf overexpression protected mice against high-fat diet–induced obesity and promoted browning of inguinal subcutaneous WAT (iWAT). Manf overexpression in liver was also associated with decreased adipose inflammation and improved insulin sensitivity and hepatic steatosis. Mechanistically, Manf could directly promote browning of white adipocytes via the p38 MAPK pathway. Blockade of p38 MAPK abolished Manf-induced browning. Consistently, liver-specific Manf knockout mice showed impaired iWAT browning and exacerbated diet-induced obesity, insulin resistance, and hepatic steatosis. Recombinant Manf reduced obesity and improved insulin resistance in both diet-induced and genetic obese mouse models. Finally, we showed that circulating Manf level was positively correlated with BMI in humans. This study reveals the crucial role of Manf in regulating thermogenesis in adipose tissue, representing a potential therapeutic target for obesity and related metabolic disorders.