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Reciprocity between Skeletal Muscle AMPK Deletion and Insulin Action in Diet-Induced Obese Mice

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posted on 21.05.2020 by Ada Admin, Louise Lantier, Ashley S. Williams, Ian M.Williams, Amanda Guerin, Deanna P. Bracy, Mickael Goelzer, Marc Foretz, Benoit Viollet, Curtis C. Hughey, David H. Wasserman
Insulin resistance due to overnutrition places a burden on energy-producing pathways in skeletal muscle (SkM). Nevertheless, energy state is not compromised. The hypothesis that the energy sensor AMP-activated protein kinase (AMPK) is necessary to offset the metabolic burden of overnutrition was tested using chow-fed and high fat (HF)-fed SkM-specific AMPKa1a2 knockout (mdKO) mice and AMPKa1a2lox/lox littermates (WT). Lean mdKO and WT mice were phenotypically similar. HF-fed mice were equally obese and maintained lean mass regardless of genotype. Results did not support the hypothesis that AMPK is protective during overnutrition. Paradoxically, mdKO mice were more insulin sensitive. Insulin-stimulated SkM glucose uptake was ~two-fold greater in mdKO mice in vivo. Furthermore, insulin signaling, SkM GLUT4 translocation, hexokinase activity, and glycolysis were increased. AMPK and insulin signaling intersect at mTOR, a critical node for cell proliferation and survival. Basal mTOR activation was reduced by 50% in HF-fed mdKO mice, but was normalized by insulin-stimulation. Mitochondrial function was impaired in mdKO mice, but energy charge was preserved by AMP deamination. Results show a surprising reciprocity between SkM AMPK signaling and insulin action that manifests with diet-induced obesity, as insulin action is preserved to protect fundamental energetic processes in the muscle.

Funding

This work was supported by National Institute of Health grant DK054902, the European Commission integrated project (LSHM-CT-2004- 005272), Agence Nationale de la Recherche (PHYSIO 2006 R06428KS), and Association Française contre les Myopathies (grant 14138).

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