Abstract
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 AMPK is necessary to offset the metabolic burden of overnutrition was tested using chow-fed and high-fat (HF)–fed SkM-specific AMPKα1α2 knockout (mdKO) mice and AMPKα1α2lox/ lox littermates (wild-type [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 approximately twofold greater in mdKO mice in vivo. Furthermore, insulin signaling, SkM GLUT4 translocation, hexokinase activity, and glycolysis were increased. AMPK and insulin signaling intersect at mam-malian target of rapamycin (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 surpris-ing reciprocity between SkM AMPK signaling and insulin action that manifests with diet-induced obesity, as insulin action is preserved to protect fundamental ener-getic processes in the muscle.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1636-1649 |
| Number of pages | 14 |
| Journal | Diabetes |
| Volume | 69 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2020 |
Bibliographical note
Funding Information:The authors thank the Vanderbilt MMPC Hormone Assay and Analytical Services Core (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] grant DK-059637) for the insulin assay and the MMPC Lipid and Lipoprotein Core for tissue lipid measurements. The GLUT4 imaging and immunohistochemistry were performed in part using the Vanderbilt Translational Pathology Core as well as the Vanderbilt University Cell Imaging Shared Resource (supported by National Institutes of Health grants CA-068485 [National Cancer Institute], DK-020593 [NIDDK], DK-058404 [NIDDK], DK-050277 [NIDDK], and EY-08126 [National Eye Institute]). The authors also acknowledge the Vanderbilt Diabetes Research and Training Center (NIDDK grant DK-020593). Funding. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant DK-054902, the European Commission Integrated Project (LSHM-CT-2004-005272), Agence Nationale de la Recherche (PHYSIO 2006 R06428KS), and Association Fran?aise contre les Myopathies (grant 14138).
Funding Information:
Acknowledgments. The authors thank the Vanderbilt MMPC Hormone Assay and Analytical Services Core (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] grant DK-059637) for the insulin assay and the MMPC Lipid and Lipoprotein Core for tissue lipid measurements. The GLUT4 imaging and immunohistochemistry were performed in part using the Vanderbilt Translational Pathology Core as well as the Vanderbilt University Cell Imaging Shared Resource (supported by National Institutes of Health grants CA-068485 [National Cancer Institute], DK-020593 [NIDDK], DK-058404 [NIDDK], DK-050277 [NIDDK], and EY-08126 [National Eye Institute]). The authors also acknowledge the Vanderbilt Diabetes Research and Training Center (NIDDK grant DK-020593). Funding. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant DK-054902, 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). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. L.L. researched data and wrote the manuscript. A.S.W., I.M.W., A.G., D.P.B., M.G., and B.V. researched data. M.F. and B.V. provided the mouse line, contributed to discussion, and reviewed the manuscript. C.C.H. and D.H.W. contributed to discussion and edited and reviewed the manuscript. L.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in oral form at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9– 13 June 2017.
Publisher Copyright:
© 2020 by the American Diabetes Association.
