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Muscle-specific Pparg deletion causes insulin resistance

Nature Medicine volume 9, pages 1491–1497 (2003)Cite this article

Abstract

Thiazolidinediones (TZDs) are insulin-sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator-activated receptor-γ (PPAR-γ). Although muscle is the major organ responsible for insulin-stimulated glucose disposal, PPAR-γ is more highly expressed in adipose tissue than in muscle. To address this issue, we used the Cre-loxP system to knock out Pparg, the gene encoding PPAR-γ, in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR-γ in muscle showed glucose intolerance and progressive insulin resistance. Using the hyperinsulinemic-euglycemic clamp technique, the in vivo insulin-stimulated glucose disposal rate (IS-GDR) was reduced by ∼80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR-γ in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs.

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Figure 1: Floxed Pparg targeting construct and muscle gene deletion.
Figure 2: Insulin and glucose tolerance in MKO mice.
Figure 3: In vivo and in vitro insulin sensitivity.
Figure 4: Effect of muscle Pparg deletion on adipose tissue and liver insulin sensitivity.
Figure 5: Effect of TZDs in MKO mice.

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Acknowledgements

The authors thank J. Arimura and M. Nelson for assistance with animal care and husbandry; B. Hansen and E. Stevens for technical assistance with manuscript preparation; and C.R. Kahn for transgenic mice expressing MCK-Cre. These studies were supported by National Institutes of Health grants DK-33651 (J.M.O.), DK-60484 (A.L.H.), 2T32 DK07044-23 (W.H.) and DK57978-24 (R.M.E.), the National Institute for Diabetes, Digestive and Kidney Diseases, National Heart, Lung and Blood Institute grant HL56989 (R.M.E.), the Hilblom Foundation (J.M.O. and R.M.E.) and the Veterans Administration Research Service. R.M.E. is an investigator of the Howard Hughes Medical Institute at the Salk Institute for Biological Sciences.

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Author notes

  1. Andrea L Hevener, Weimin He and Yaacov Barak: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, 92093, California, USA

    Andrea L Hevener, Weimin He, Jamie Le, Gautam Bandyopadhyay, Jason Wilkes & Jerrold Olefsky

  2. Department of Biology, University of California, San Diego, La Jolla, 92093, California, USA

    Peter Olson

  3. Jackson Laboratory, Bar Harbor, 04609, Maine, USA

    Yaacov Barak

  4. Gene Expression Laboratory, The Salk Institute, La Jolla, 92093, California, USA

    Yaacov Barak, Peter Olson & Ronald M Evans

  5. Howard Hughes Medical Institute, The Salk Institute, La Jolla, 92093, California, USA

    Ronald M Evans

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Correspondence to Ronald M Evans or Jerrold Olefsky.

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Hevener, A., He, W., Barak, Y. et al. Muscle-specific Pparg deletion causes insulin resistance. Nat Med 9, 1491–1497 (2003). https://doi.org/10.1038/nm956

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