1. Liver-specific overexpression of SIRT3 enhances oxidative metabolism, but does not impact metabolic defects induced by high fat feeding in mice.
- Author
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Osborne B, Reznick J, Wright LE, Sinclair DA, Cooney GJ, and Turner N
- Subjects
- Animals, Mice, Mice, Knockout, Oxidative Stress, Triglycerides metabolism, Insulin Resistance, Liver metabolism, Sirtuin 3 genetics, Sirtuin 3 metabolism
- Abstract
The mitochondrial enzyme SIRT3 is an NAD
+ -dependent deacetylase important in cell metabolism, and a decline in its protein expression or activity has been linked with insulin resistance in obesity, ageing and type 2 diabetes. While studies in SIRT3 knockout mice have dramatically improved our understanding of the function of SIRT3, the impact of increasing SIRT3 levels remains under-examined. In this study we investigated the effects of liver-specific SIRT3 overexpression in mice on mitochondrial function and metabolic profile in both isolated hepatocytes and in vivo. Primary hepatocytes overexpressing SIRT3 displayed increased oxygen consumption and a reduction in triglyceride accumulation. In mice with hepatic SIRT3 overexpression, increased fasting β-hydroxybutyrate levels were observed, coupled with an increase in oxygen consumption in isolated mitochondria and increased substrate utilization in liver homogenates. However, metabolic profiling of mice exposed to either chow or high-fat diet revealed no effect of hepatic SIRT3 overexpression on glucose tolerance, body composition or tissue triglyceride accumulation. These findings suggest limited whole-body benefit of increasing hepatic SIRT3 during the development of diet-induced insulin resistance., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: D.A.S. is a founder, equity owner, advisor to, director of, board member of, consultant to, investor in and/or inventor on patents licensed to RevereBiosensors, UpRNA, GlaxoSmithKline, Wellom-ics, DaVinci Logic, InsideTracker (Segterra), Caudalie, Animal Biosciences, Longwood Fund, Catalio Capital Management, Frontier Acquisition Corporation, AFAR (American Federation for Aging Research), Life Extension Advocacy Foundation (LEAF), Cohbar, Galilei, EMD Millipore, Zymo Research, Immetas, Bayer Crop Science, EdenRoc Sciences (and affiliates Arc-Bio, Dovetail Genomics, Claret Bioscience, MetroBiotech, and Liberty Biosecurity), LifeBiosciences (and affili-ates Iduna, Senolytic Therapeutics, Selphagy, Jumpstart Fertility, Continuum Biosciences, and Al-terity), ATAI Life Sciences, Levels Health, and Bold Capital. D.A.S. is an inventor on a patent ap-plication filed by Mayo Clinic and Harvard Medical School that has been licensed to Elysium Health. More information at https://sinclair.hms.harvard.edu/david-sinclairs-affiliations. The remaining authors note no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)- Published
- 2022
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