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Depletion of TBC1D4 improves the metabolic exercise response by overcoming genetically induced peripheral insulin resistance

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posted on 2024-04-12, 20:55 authored by Christian Springer1, Christian Binsch, Deborah Weide, Laura Toska, Anna Lena Cremer, Heiko Backes, Anna K. Scheel, Lena Espelage, Jörg Kotzka, Sebastian Sill, Anette Kurowski, Daebin Kim, Sandra Karpinski, Theresia M. Schnurr, Torben Hansen, Sonja Hartwig, Stefan Lehr, Sandra Cames, Jens Brüning, Matthias Lienhard, Ralf Herwig, Stefan Börno, Bernd Timmermann, Hadi Al-Hasani, Alexandra Chadt

The RabGTPase-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 (HFD), we show that already a 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 (iBAT) and WAT from trained D4KO mice. Thus, chronic exercise is able to overcome the genetically induced insulin resistance caused by the Tbc1d4-depletion. Gene variants in TBC1D4 may be relevant in future precision medicine as determinants of exercise response.

Funding

This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (DFG-RTG 2576 vivid; CH1659 to AC), Deutsche Diabetes Gesellschaft (DDG), EFSD/Novo Nordisk Program for Diabetes Research, and the Ministry of Science and Research of the State North Rhine-Westphalia (MIWF NRW) and the German Federal Ministry of Health (BMG).

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