The Rab-GTPase–activating protein (RabGAP) TBC1D4 (AS160) represents a key component in the regulation of glucose transport into skeletal muscle and white adipose tissue (WAT) and is therefore crucial during the development of insulin resistance and type 2 diabetes. Increased daily activity has been shown to be associated with improved postprandial hyperglycemia in allele carriers of a loss-of-function variant in the human TBC1D4 gene. Using conventional Tbc1d4-deficient mice (D4KO) fed a high-fat diet, we show that moderate endurance exercise training leads to substantially improved glucose and insulin tolerance and enhanced expression levels of markers for mitochondrial activity and browning in WAT from D4KO animals. Importantly, in vivo and ex vivo analyses of glucose uptake revealed increased glucose clearance in interscapular brown adipose tissue and WAT from trained D4KO mice. Thus, chronic exercise is able to overcome the genetically induced insulin resistance caused by Tbc1d4 depletion. Gene variants in TBC1D4 may be relevant in future precision medicine as determinants of exercise response.

Article Highlights
  • The study was conducted to unravel the mechanistic basis of exercise-mediated improvements of insulin resistance.

  • We wanted to answer whether genetically induced insulin resistance as present upon deletion of the insulin signaling factor TBC1D4 can be rescued by endurance exercise training in Tbc1d4-deficient mice.

  • We show that deletion of Tbc1d4 leads to an enhanced exercise response as presented by improved insulin sensitivity, especially in the adipose tissue.

  • TBC1D4 gene variants may serve as potential predictive markers for precision medicine approaches.

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