Sirt6 deletion in hepatocytes increases insulin sensitivity of female mice by enhancing ERα expression

Abstract

Sirtuin 6 (Sirt6), a NAD+‐dependent protein deacetylase, is involved in hepatic glucose metabolism and insulin sensitivity, which impact metabolic homeostasis. In this paper, we discover that Sirt6 affects the insulin sensitivity of mice in a gender‐dependent manner; few studies have been conducted on this issue. Based on reports revealing the influences of sex hormones on insulin signaling, this investigation explores the mechanism by which Sirt6 regulates the estrogen pathway and disrupts insulin signal transduction. Hepatocyte‐specific Sirt6 knockout (Sirt6HKO) mice were generated to investigate the function of Sirt6 in hepatocytes. Mice were castrated or spayed to eliminate sex hormones. Insulin sensitivity was assessed via an insulin tolerance test (ITT) in vivo. The interaction of Sirt6 with the estrogen pathway and their impacts on insulin signal transduction were revealed by immunoblot and immunoprecipitation. Sirt6 deletion in hepatocytes significantly enhanced insulin sensitivity and signal transduction in female mice but not in male or spayed female mice as demonstrated by ITT and the phosphorylation level of Akt in the liver. We also identified upregulation of p300, ERα, and interaction of ERα with p85 in the liver of female Sirt6HKO mice. Additionally, Sirt6 was found to inhibit ERα protein stability in a p300‐dependent manner without interacting directly with ERα. Our findings show that hepatic Sirt6 downregulates the ERα protein level in a p300‐dependent manner and thus disturbs estrogen‐induced improvement in insulin sensitivity in the liver, which may partially explain the gender difference in insulin sensitivity.

Total Sesquiterpene Glycosides from Loquat Leaves Ameliorate HFD‐Induced Insulin Resistance by Modulating IRS‐1/GLUT4, TRPV1, and SIRT6/Nrf2 Signaling Pathways

“…Furthermore, it has been regarded as a therapeutic agent for IR [ 26 , 27 ]. SIRT6 deficiency could make diet-induced IR heavier [ 28 ]. SIRT6 has been well established to promote nuclear factor erythroid 2-related factor 2 (Nrf2) binding the antioxidant response elements (AREs) and to protect cells from oxidative stress [ 29 ].…”

Emerging roles of SIRT6 in human diseases and its modulators

“…In this context, hepatic SIRT6 reduced p300 to downregulate the protein level of estrogen receptor ERα, and thus attenuated estrogen‐induced activation of PI3K and blocked insulin signal transduction to eventually reduce insulin sensitivity in the liver. Consistently, SIRT6 deletion in hepatocytes significantly increased insulin sensitivity, especially in female mice, by improving the expression of ERα 183 …”

“…Along this line, the protective function of SIRT6 is regulated by nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2), whose overexpression increases the intracellular NAD + level and then augments cardiomyocytes hypertrophic prevention by activating SIRT6 204 . SIRT6 was also observed to suppress PI3K/Akt signaling to reduce p300 expression via promoting its degradation 183,205,206 . The downregulation of p300 protein subsequently inhibited the transcriptional activity of NF‐κB p65 subunit, hence protecting cardiomyocytes from hypertrophy by angiotensin II (Ang II) or phenylephrine stimulation 205,207 .…”

Sirtuin 6 supra‐physiological overexpression in hypothalamic pro‐opiomelanocortin neurons promotes obesity via the hypothalamus‐adipose axis

“…For example, deletion of Sirt6 in adipose tissues decreased lipolysis and thermogenesis, leading to obesity 19,38 ; hepatic‐specific deletion of Sirt6 aggravated liver steatosis and insulin resistance, 16,39 but moderate and physiological overexpression of Sirt6 enhanced insulin sensitivity in skeletal muscle and liver 40 . However, studies also showed that Sirt6 inhibition significantly improved glucose tolerance in a type 2 diabetes mouse model, 41 and Sirt6 deletion in hepatocytes increased insulin sensitivity of female mice 42 . In the present study, Sirt6 overexpression specifically in hypothalamic POMC neurons exacerbated energy imbalance and metabolic disorders.…”