The Role of Sirt6 in Obesity and Diabetes

Abstract

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.

Keywords: LiPo; Sirt6; diabetes mellitus; gluconeogenesis; obesity; type 2.

Figure 1

The role of Sirt6 in glucose metabolism. Sirt6 inhibits recruitment of Hif-1α to its target gene promoters, increases mitochondrial respiration and inhibits glycolysis. Sirt6 binds to and activates GCN5, inhibits the acetylation of PGC-1α, and decreases the expression of gluconeogenic genes. Sirt6 can specifically interact with FoxO1, decrease FoxO1 acetylation and phosphorylation level, and inhibit the interaction between FoxO1 and its downstream gene promoters, thereby reducing the expression of gluconeogenic genes. Sirt6 protects against β-cell dysfunction and apoptosis and increases insulin secretion.

Figure 2

The role of Sirt6 in lipid metabolism. Sirt6 represses the mRNA expression of SREBP1/2 and inhibits the cleavage of SREBPs into their active forms. Sirt6 activates AMPK (by increasing the AMP/ATP ratio and activating LKB), which phosphorylates and inactivates SREBP. Sirt6 can be recruited by FoxO3a to the Pcsk9 promoter, suppress its gene expression and decrease the level of LDL-cholesterol. Sirt6 downregulates miR-122 by deacetylating H3K56, reduces miR-122 expression, and increases fatty acid β-oxidation. Sirt6 also specifically interacts with FoxO1, decreases FoxO1 acetylation and phosphorylation, and promotes the interaction between FoxO1 and the promoter of its downstream gene, ATGL, thereby increasing ATGL expression and inducing lipolysis in adipose tissue. Sirt6 inhibits KIF5C gene expression and impairs adipogenesis. Sirt6 regulates phospho-ATF2 (p-ATF2) binding to the PGC-1α promoter and subsequently affects the thermogenic program. Sirt6 regulates the circadian rhythm in the liver by maintaining a proper cyclic recruitment of CLOCK/BMAL1.