Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism
| Autor: | Jonathan M. Dreyfuss, Manway Liu, Niels Jessen, Walt Gall, Tanner Boes, Irini Manoli, Elvira Isganaitis, Carles Lerin, Grace Daher, Simon Kasif, Kirk Beebe, Mary-Elizabeth Patti, Charles P. Venditti, Justin R. Sysol, Ana Luísa De Sousa-Coelho, Allison B. Goldfine, Laurie J. Goodyear |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
lcsh:Internal medicine medicine.medical_specialty Branched-chain amino acid Biology 03 medical and health sciences chemistry.chemical_compound Insulin resistance Internal medicine medicine Journal Article Glucose homeostasis BCAA lcsh:RC31-1245 Molecular Biology Beta oxidation TCA cycle Fatty acid metabolism Skeletal muscle Lipid metabolism Cell Biology Metabolism medicine.disease Insulin sensitivity 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry Fatty acid oxidation Original Article |
| Zdroj: | Molecular Metabolism Lerin, C, Goldfine, A B, Boes, T, Liu, M, Kasif, S, Dreyfuss, J M, De Sousa-Coelho, A L, Daher, G, Manoli, I, Sysol, J R, Isganaitis, E, Jessen, N, Goodyear, L J, Beebe, K, Gall, W, Venditti, C P & Patti, M-E 2016, ' Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism ', Molecular Metabolism, vol. 5, no. 10, pp. 926-36 . https://doi.org/10.1016/j.molmet.2016.08.001 Molecular Metabolism, Vol 5, Iss 10, Pp 926-936 (2016) |
| ISSN: | 2212-8778 |
| Popis: | Objective Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear. Methods To identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (SI, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis. Results Our data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding. Conclusions Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D. Highlights • Human insulin resistance is associated with perturbed muscle BCAA metabolism. • Experimental modulation of BCAA metabolic flux alters fatty acid oxidation in vitro. • Mut heterozygosis leads to increased body weigh and muscle TAG accumulation in mice. |
| Databáze: | OpenAIRE |
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