SIRT3 Is Crucial for Maintaining Skeletal Muscle Insulin Action and Protects Against Severe Insulin Resistance in High-Fat–Fed Mice

摘要: Protein hyperacetylation is associated with glucose intolerance and insulin resistance, suggesting that the enzymes regulating acetylome play a role in this pathological process. Sirtuin 3 (SIRT3), primary mitochondrial deacetylase, has been linked to energy homeostasis. Thus, it hypothesized dysregulation of acetylation state, via genetic deletion SIRT3, will amplify deleterious effects high-fat diet (HFD). Hyperinsulinemic-euglycemic clamp experiments show, for first time, mice lacking SIRT3 exhibit increased resistance due defects skeletal muscle uptake. Permeabilized fibers from HFD-fed knockout (KO) showed tricarboxylic acid cycle substrate–based respiration decreased while fatty acid–based increased, reflecting fuel switch acids. Consistent reduced uptake, hexokinase II (HKII) binding mitochondria KO mice, HKII activity. These results show absence causes profound impairments insulin-stimulated creating an reliance on Insulin action was not impaired lean mice. This suggests protects against dietary by facilitating disposal function.