1. Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension.
- Author
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Yu D, Tomasiewicz JL, Yang SE, Miller BR, Wakai MH, Sherman DS, Cummings NE, Baar EL, Brinkman JA, Syed FA, and Lamming DW
- Subjects
- Adiposity drug effects, Animals, Caloric Restriction methods, Energy Intake drug effects, Energy Intake physiology, Humans, Longevity drug effects, Longevity physiology, Mice, Mice, Inbred C57BL, Signal Transduction drug effects, Signal Transduction physiology, Sirolimus pharmacology, Adiposity physiology, Insulin metabolism, Insulin Resistance physiology, Mechanistic Target of Rapamycin Complex 2 metabolism
- Abstract
Calorie restriction (CR) extends the healthspan and lifespan of diverse species. In mammals, a broadly conserved metabolic effect of CR is improved insulin sensitivity, which may mediate the beneficial effects of a CR diet. This model has been challenged by the identification of interventions that extend lifespan and healthspan yet promote insulin resistance. These include rapamycin, which extends mouse lifespan yet induces insulin resistance by disrupting mTORC2 (mechanistic target of rapamycin complex 2). Here, we induce insulin resistance by genetically disrupting adipose mTORC2 via tissue-specific deletion of the mTORC2 component Rictor (AQ-RKO). Loss of adipose mTORC2 blunts the metabolic adaptation to CR and prevents whole-body sensitization to insulin. Despite this, AQ-RKO mice subject to CR experience the same increase in fitness and lifespan on a CR diet as wild-type mice. We conclude that the CR-induced improvement in insulin sensitivity is dispensable for the effects of CR on fitness and longevity., (Published by Elsevier Inc.)
- Published
- 2019
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