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.
Highlights
Calorie restriction (CR), a dietary regimen in which calories are reduced without causing malnutrition, extends the lifespan of many diverse species and is the gold standard for interventions that promote the health and longevity of mammals (Lamming and Anderson, 2014; Madeo et al, 2019)
We found that RICTOR protein expression was substantially reduced in the adipose tissues of AQ-RKO mice, including the inguinal white adipose tissue (WAT) and epididymal WAT, but was not altered in other organs, including liver and skeletal muscle (Figure 1A)
We found that AQ-RKO mice of both sexes were glucose tolerant (Figure 1F), but, as we anticipated given the established role of adipose tissue in insulin-stimulated glucose clearance (Rosen and Spiegelman, 2006), we observed that AQ-RKO mice were insulin resistant, with a more pronounced effect in male mice (Figure 1G)
Summary
Calorie restriction (CR), a dietary regimen in which calories are reduced without causing malnutrition, extends the lifespan of many diverse species and is the gold standard for interventions that promote the health and longevity of mammals (Lamming and Anderson, 2014; Madeo et al, 2019). Many dietary and pharmaceutical interventions that extend mammalian lifespan and healthspan likewise promote insulin sensitivity, while there is a well-known association of insulin resistance with diabetes and poor health. Given the central role of the insulin signaling pathway in the lifespan of worms, flies, and mammals (Lamming, 2014; Kenyon, 2001), improved insulin sensitivity has been proposed as an essential mechanism by which a CR diet extends mammalian lifespan (Lamming and Anderson, 2014). While the effects of CR are systemic, some of its most prominent effects are on adipose tissue; CR reduces adiposity in mammals, mobilizing fat stores in white adipose tissue (WAT) while activating WAT lipogenesis, which is associated with improved systemic insulin sensitivity and metabolic health (Herman et al, 2012; Chen et al, 2008; Bruss et al, 2010)
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