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Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice

Nature Medicine volume 6, pages 1115–1120 (2000)Cite this article

Abstract

To determine whether uncoupling respiration from oxidative phosphorylation in skeletal muscle is a suitable treatment for obesity and type 2 diabetes, we generated transgenic mice expressing the mitochondrial uncoupling protein (Ucp) in skeletal muscle. Skeletal muscle oxygen consumption was 98% higher in Ucp-L mice (with low expression) and 246% higher in Ucp-H mice (with high expression) than in wild-type mice. Ucp mice fed a chow diet had the same food intake as wild-type mice, but weighed less and had lower levels of glucose and triglycerides and better glucose tolerance than did control mice. Ucp-L mice were resistant to obesity induced by two different high-fat diets. Ucp-L mice fed a high-fat diet had less adiposity, lower levels of glucose, insulin and cholesterol, and an increased metabolic rate at rest and with exercise. They were also more responsive to insulin, and had enhanced glucose transport in skeletal muscle in the setting of increased muscle triglyceride content. These data suggest that manipulating respiratory uncoupling in muscle is a viable treatment for obesity and its metabolic sequelae.

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Figure 1: Expression of the Ucp transgene is limited to skeletal muscle.
Figure 2: Glucose- and insulin-tolerance tests in mice fed a chow diet.
Figure 3: Effects of high-fat diet on body weight in mice.
Figure 4: Enhanced glucose tolerance and insulin responsiveness in Ucp-L mice fed a ‘Western’ diet.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (HL58427, DK53198, AG00425 and AG14658), the Washington University Clinical Nutrition Research Unit (DK56341) and the Washington University Diabetes Research and Training Center (DK20579).

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Author notes

  1. Bing Li and Lorraine A. Nolte: B.L. & L.N. contributed equally to this work.

Authors and Affiliations

  1. Departments of Medicine and Cell Biology & Physiology Division of Atherosclerosis, Division of Geriatrics and Gerontology, Nutrition, and Lipid Research, Center for Cardiovascular Research, Washington University School of Medicine, Box 8046, 660 South Euclid Avenue, St. Louis, 63110, Missouri, USA

    Bing Li, Lorraine A. Nolte, Jeong-Sun Ju, Dong Ho Han, Trey Coleman, John O. Holloszy & Clay F. Semenkovich

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  1. Bing Li
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Correspondence to Clay F. Semenkovich.

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Li, B., Nolte, L., Ju, JS. et al. Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice. Nat Med 6, 1115–1120 (2000). https://doi.org/10.1038/80450

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