Abstract
Sirt1 is a NAD(+)-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. To assess this idea, we generated Sirt1 neuron-specific knockout (SINKO) mice. On both standard chow and HFD, SINKO mice were more insulin sensitive than Sirt1(f/f) mice. Thus, SINKO mice had lower fasting insulin levels, improved glucose tolerance and insulin tolerance, and enhanced systemic insulin sensitivity during hyperinsulinemic euglycemic clamp studies. Hypothalamic insulin sensitivity of SINKO mice was also increased over controls, as assessed by hypothalamic activation of PI3K, phosphorylation of Akt and FoxO1 following systemic insulin injection. Intracerebroventricular injection of insulin led to a greater systemic effect to improve glucose tolerance and insulin sensitivity in SINKO mice compared with controls. In line with the in vivo results, insulin-induced AKT and FoxO1 phosphorylation were potentiated by inhibition of Sirt1 in a cultured hypothalamic cell line. Mechanistically, this effect was traced to a reduced effect of Sirt1 to directly deacetylate and repress IRS-1 function. The enhanced central insulin signaling in SINKO mice was accompanied by increased insulin receptor signal transduction in liver, muscle, and adipose tissue. In summary, we conclude that neuronal Sirt1 negatively regulates hypothalamic insulin signaling, leading to systemic insulin resistance. Interventions that reduce neuronal Sirt1 activity have the potential to improve systemic insulin action and limit weight gain on an obesigenic diet.
Highlights
Sirtuin 1 (Sirt1) is a NADϩ-dependent class III deacetylase and a cellular energy sensor
Sirt1 Neuron-specific Knock-out Mice (SINKO Mice)—To investigate the function of neuronal Sirt1, we generated specific knockout (SINKO) mice using the synapsin I Cre-LoxP system
Quantitative PCR for measurement of Sirt1 exon 4 showed that brain Sirt1 deletion was regional, with markedly reduced mRNA abundance in spinal cord, brain stem, hypothalamus, diencephalon, and hippocam
Summary
Sirt is a NADϩ-dependent class III deacetylase and a cellular energy sensor. Results: Selective removal of Sirt in neurons causes increased central and systemic insulin sensitivity. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt activity plays a role in the central regulation of energy balance and glucose metabolism To assess this idea, we generated Sirt neuron-specific knockout (SINKO) mice. On a mixed genetic background, Ramadori et al, reported that selective knock-out (KO) of Sirt in pro-opiomelanocortin (POMC) neurons, a key hypothalamic neuronal subset for energy homeostasis, decreases energy expenditure and increases susceptibility to diet-induced obesity (DIO) in mice [7] Both intracerebroventricular (i.c.v.) injection of EX-527, a specific Sirt inhibitor, and deletion of Sirt in Agouti-related peptide (AgRP) neurons (situated adjacent to POMC cells in the hypothalamic arcuate nucleus (ARC), cause decreases of food intake and body weight in mice and rats [8, 9]. The improved systemic insulin sensitivity of SINKO mice was associated with improved CNS insulin signaling in the hypothalamus These findings indicate that neuronal Sirt plays a physiological role to inhibit both hypothalamic insulin sensitivity and whole body glucose homeostasis
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