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SIRT3 is crucial for maintaining skeletal muscle insulin action and protects
against severe insulin resistance in high fat fed mice.

Authors	Lantier L, Williams AS, Williams IM, Yang KK, Bracy DP, Goelzer M, James FD, Gius D, Wasserman DH
Submitted By	David Wasserman on 7/24/2015
Status	Published
Journal	Diabetes
Year	2015
Date Published	5/6/2015
Volume : Pages	Not Specified : Not Specified
PubMed Reference	25948682
Abstract	Protein hyperacetylation is associated with glucose intolerance and insulin resistance suggesting that the enzymes regulating the acetylome play a role in this pathological process. SIRT3, the primary mitochondrial deacetylase, has been linked to energy homeostasis. Thus, it is hypothesized that the dysregulation of the mitochondrial acetylation state, via genetic deletion of SIRT3, will amplify the deleterious effects of a high fat diet (HFD). Hyperinsulinemic-euglycemic clamp experiments show, for the first time, that mice lacking SIRT3 exhibit increased insulin resistance due to defects in skeletal muscle glucose uptake. Permeabilized muscle fibers from HF-fed SIRT3 KO mice showed that TCA cycle substrate-based respiration is decreased while fatty acid-based respiration is increased, reflecting a fuel switch from glucose to fatty acids. Consistent with reduced muscle glucose uptake, hexokinase II (HKII) binding to the mitochondria is decreased in muscle from HF-fed SIRT3 KO mice, suggesting decreased HKII activity. These results show that absence of SIRT3 in HF-fed causes profound impairments in insulin-stimulated muscle glucose uptake, creating an increased reliance on fatty acids. Insulin action was not impaired in the lean SIRT3 KO mice. This suggests that SIRT3 protects against dietary insulin resistance by facilitating glucose disposal and mitochondrial function.

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