Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension

• Published in: Cell reports (Cambridge) Vol. 29; no. 1; pp. 236 - 248.e3
• Main Authors: Yu, Deyang, Tomasiewicz, Jay L., Yang, Shany E., Miller, Blake R., Wakai, Matthew H., Sherman, Dawn S., Cummings, Nicole E., Baar, Emma L., Brinkman, Jacqueline A., Syed, Faizan A., Lamming, Dudley W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2019; Elsevier
• Subjects: adipose; Adiposity - drug effects; Adiposity - physiology; Animals; Caloric Restriction - methods; calorie restriction; Energy Intake - drug effects; Energy Intake - physiology; fitness; frailty; healthspan; Humans; Insulin - metabolism; Insulin Resistance - physiology; insulin sensitivity; lifespan; lipogenesis; Longevity - drug effects; Longevity - physiology; Mechanistic Target of Rapamycin Complex 2 - metabolism; Mice; Mice, Inbred C57BL; mTORC2; Rictor; Signal Transduction - drug effects; Signal Transduction - physiology; Sirolimus - pharmacology; insulin sensitivity; frailty; calorie restriction; fitness; lifespan; Rictor; adipose; lipogenesis; mTORC2; healthspan
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.08.084

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. [Display omitted] •Calorie restriction (CR) extends lifespan and improves insulin sensitivity•Mice lacking adipose mTORC2 are insulin resistant, even on a CR diet•CR promotes fitness and longevity in mice lacking adipose mTORC2•Improved organismal insulin sensitivity does not mediate the beneficial effects of CR Calorie restriction (CR) diets improve insulin sensitivity and extend lifespan. Yu et al. find that although mice lacking mTORC2 in adipose remain insulin resistant on a CR diet, their fitness and longevity increases similarly to wild-type mice.