Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension
Deyang Yu,
Jay L. Tomasiewicz,
Shany E. Yang,
Blake R. Miller,
Matthew H. Wakai,
Dawn S. Sherman,
Nicole E. Cummings,
Emma L. Baar,
Jacqueline A. Brinkman,
Faizan A. Syed,
Dudley W. Lamming
Affiliations
Deyang Yu
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; Molecular and Environmental Toxicology Program, University of Wisconsin-Madison, Madison, WI, USA
Jay L. Tomasiewicz
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
Shany E. Yang
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
Blake R. Miller
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
Matthew H. Wakai
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
Dawn S. Sherman
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
Nicole E. Cummings
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA
Emma L. Baar
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
Jacqueline A. Brinkman
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
Faizan A. Syed
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
Dudley W. Lamming
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; Molecular and Environmental Toxicology Program, University of Wisconsin-Madison, Madison, WI, USA; Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA; University of Wisconsin Carbone Cancer Center, Madison, WI, USA; Corresponding author
Summary: 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. : 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. Keywords: mTORC2, calorie restriction, healthspan, insulin sensitivity, frailty, fitness, lifespan, adipose, lipogenesis, Rictor
