Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues.

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.

• Authors: Min Lu, David A Sarruf, Pingping Li, Olivia Osborn, Manuel Sanchez-Alavez, Saswata Talukdar, Ai Chen, Gautam Bandyopadhyay, Jianfeng Xu, Hidetaka Morinaga, Kevin Dines, Steven Watkins, Karl Kaiyala, Michael W Schwartz, Jerrold M Olefsky
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 15 Pg. 10722-35 (Apr 12 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23457303 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Foxo1 protein, mouse
• Hypoglycemic Agents
• Insulin
• Insulin Receptor Substrate Proteins
• Irs1 protein, mouse
• Nerve Tissue Proteins
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Sirt1 protein, mouse
• Sirtuin 1
• Glucose

Topics

• Animals
• Cells, Cultured
• Energy Metabolism (physiology)
• Forkhead Box Protein O1
• Forkhead Transcription Factors (genetics, metabolism)
• Glucose (genetics, metabolism)
• Hypoglycemic Agents (metabolism, pharmacology)
• Hypothalamus (metabolism)
• Insulin (genetics, metabolism, pharmacology)
• Insulin Receptor Substrate Proteins (genetics, metabolism)
• Insulin Resistance (physiology)
• Mice
• Mice, Knockout
• Nerve Tissue Proteins (genetics, metabolism)
• Organ Specificity
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphorylation (drug effects, physiology)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction (drug effects, physiology)
• Sirtuin 1 (genetics, metabolism)