The Emerging Role of SIRT7 in Glucose and Lipid Metabolism.

Sirtuins (SIRT1-7 in mammals) are a family of NAD+-dependent lysine deacetylases and deacylases that regulate diverse biological processes, including metabolism, stress responses, and aging. SIRT7 is the least well-studied member of the sirtuins, but accumulating evidence has shown that SIRT7 plays critical roles in the regulation of glucose and lipid metabolism by modulating many target proteins in white adipose tissue, brown adipose tissue, and liver tissue. This review focuses on the emerging roles of SIRT7 in glucose and lipid metabolism in comparison with SIRT1 and SIRT6. We also discuss the possible implications of SIRT7 inhibition in the treatment of metabolic diseases such as type 2 diabetes and obesity.

SIRT7 suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions in mice.

Brown adipose tissue plays a central role in the regulation of the energy balance by expending energy to produce heat. NAD+-dependent deacylase sirtuins have widely been recognized as positive regulators of brown adipose tissue thermogenesis. However, here we reveal that SIRT7, one of seven mammalian sirtuins, suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions. Whole-body and brown adipose tissue-specific Sirt7 knockout mice have higher body temperature and energy expenditure. SIRT7 deficiency increases the protein level of UCP1, a key regulator of brown adipose tissue thermogenesis. Mechanistically, we found that SIRT7 deacetylates insulin-like growth factor 2 mRNA-binding protein 2, an RNA-binding protein that inhibits the translation of Ucp1 mRNA, thereby enhancing its inhibitory action on Ucp1. Furthermore, SIRT7 attenuates the expression of batokine genes, such as fibroblast growth factor 21. In conclusion, we propose that SIRT7 serves as an energy-saving factor by suppressing brown adipose tissue functions.

SIRT7 Deficiency Protects against Aging-Associated Glucose Intolerance and Extends Lifespan in Male Mice.

Sirtuins (SIRT1-7 in mammals) are evolutionarily conserved nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases that regulate fundamental biological processes including aging. In this study, we reveal that male Sirt7 knockout (KO) mice exhibited an extension of mean and maximum lifespan and a delay in the age-associated mortality rate. In addition, aged male Sirt7 KO mice displayed better glucose tolerance with improved insulin sensitivity compared with wild-type (WT) mice. Fibroblast growth factor 21 (FGF21) enhances insulin sensitivity and extends lifespan when it is overexpressed. Serum levels of FGF21 were markedly decreased with aging in WT mice. In contrast, this decrease was suppressed in Sirt7 KO mice, and the serum FGF21 levels of aged male Sirt7 KO mice were higher than those of WT mice. Activating transcription factor 4 (ATF4) stimulates Fgf21 transcription, and the hepatic levels of Atf4 mRNA were increased in aged male Sirt7 KO mice compared with WT mice. Our findings indicate that the loss of SIRT7 extends lifespan and improves glucose metabolism in male mice. High serum FGF21 levels might be involved in the beneficial effect of SIRT7 deficiency.

HNF1α controls glucagon secretion in pancreatic α-cells through modulation of SGLT1.

Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor required for normal insulin secretion and maintenance of ß-cell number in the pancreas. HNF1α is also expressed in pancreatic α-cells, but its role in these cells is unknown. The aim of this study was to clarify the role of HNF1α in α-cells. Male Hnf1a+/- mice with a mixed background were backcrossed to outbred ICR mice. Glucose tolerance, glucagon and insulin secretion, islet histology, and gene expression were investigated in ICR Hnf1a-/- and Hnf1a+/+ mice. Regulation of Slc5a1 (encoding sodium glucose cotransporter 1 [SGLT1]) expression by HNF1α and the effect of SGLT1 inhibition on glucagon secretion were also explored. ICR Hnf1a-/- mice were glucose intolerant and exhibited impaired glucose-stimulated insulin secretion. The ß-cell area of ICR mice was decreased in Hnf1a-/- mice, but the α-cell area in the pancreas was similar between Hnf1a-/- and Hnf1a+/+ mice. Hnf1a-/- mice showed higher fasting glucagon levels and exhibited inadequate suppression of glucagon after glucose load. In addition, glucagon release in response to hypoglycemia was impaired in Hnf1a-/- mice, and glucagon secretion after 1.1 mM glucose administration, was also decreased in Hnf1a-/- islets. Slc5a1 expression was decreased in Hnf1a-/- islets, while HNF1α activated the Slc5a1 promoter in αTC1-6 cells. Inhibition of SGLT1 suppressed 1.1 mM glucose-stimulated glucagon secretion in islets and αTC1-6 cells, but SGLT1 inhibition had no additional inhibitory effect in HNF1α-deficient cells. Our findings indicate that HNF1α modulates glucagon secretion in α-cells through the regulation of Slc5a1.