The NAD + -dependent deacetylase SIRT2 is unique amongst sirtuins as it is effective in the cytosol, as well as the mitochondria. Defining the role of cytosolic acetylation state in specific tissues is difficult since even physiological effects at the whole body level are unknown. We hypothesized that genetic SIRT2 knockout (KO) would lead to impaired insulin action, and that this impairment would be worsened in HF fed mice. Insulin sensitivity was tested using the hyperinsulinemic-euglycemic clamp in SIRT2 KO mice and WT littermates. SIRT2 KO mice exhibited reduced skeletal muscle insulin-induced glucose uptake compared to lean WT mice, and this impairment was exacerbated in HF SIRT2 KO mice. Liver insulin sensitivity was unaffected in lean SIRT2 KO mice. However, the insulin resistance that accompanies HF-feeding was worsened in SIRT2 KO mice. It was notable that the effects of SIRT2 KO were largely disassociated from cytosolic acetylation state, but were closely linked to acetylation state in the mitochondria. SIRT2 KO led to an increase in body weight that was due to increased food intake in HF fed mice. In summary, SIRT2 deletion in vivo reduces muscle insulin sensitivity and contributes to liver insulin resistance by a mechanism that is unrelated to cytosolic acetylation state. Mitochondrial acetylation state and changes in feeding behavior that result in increased body weight correspond to the deleterious effects of SIRT2 KO on insulin action.
Bibliographical noteFunding Information:
This work was supported by NIH-NIDDK grants DK054902, DK050277. DG is supported by 2R01CA152601-A1, 1R01CA152799-01A1, 1R01CA168292-01A1, 1R01CA214025-01, the Avon Foundation for Breast Cancer Research, the Lynn Sage Cancer Research Foundation, the Zell Family Foundation, the Chicago Biomedical Consortium, and the Searle Funds at The Chicago Community Trust. The mouse plasma insulin and leptin assays were performed by the VUMC Hormone Assay and Analytical Services Core supported by NIH grant DK059637. We also acknowledge DK020593. The indirect calorimetry experiments were carried out at the Vanderbilt Mouse Metabolic Phenotyping Center (MMPC), supported by grants DK059637 and 1S10RR028101-01. The ANCOVA analysis was provided by the NIDDK MMPC Consortium supported by DK076169. The mouse plasma insulin and leptin assays were performed by the Vanderbilt Mouse Metabolic Phenotyping Center (MMPC) Hormone Assay and Analytical Core. The indirect calorimetry experiments were carried out at the Vanderbilt MMPC. The ANCOVA analysis was provided by the NIDDK MMPC Consortium. We acknowledge the Vanderbilt Diabetes Research and Training Center.
© 2018 Lantier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.