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Dexamethasone induction of hypertension and diabetes is PPAR-α dependent in LDL receptor–null mice

Nature Medicine volume 9, pages 1069–1075 (2003)Cite this article

Abstract

Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator–activated receptor-α (PPAR-α) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr−/−), with (Ppara+/+) or without (Ppara−/−) PPAR-α, were treated chronically with dexamethasone. Ppara+/+, but not Ppara−/−, mice developed hyperglycemia, hyperinsulinemia and hypertension. Similar effects on glucose metabolism were seen in a different model using C57BL/6 mice. Hepatic gluconeogenic gene expression was increased and insulin-mediated suppression of endogenous glucose production was less effective in dexamethasone-treated Ppara+/+ mice. Adenoviral reconstitution of PPAR-α in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara−/− mice induced hyperglycemia, hyperinsulinemia and increased gluconeogenic gene expression. It also increased blood pressure, renin activity, sympathetic nervous activity and renal sodium retention. Human hepatocytes treated with dexamethasone and the PPAR-α agonist Wy14,643 induced PPARA and gluconeogenic gene expression. These results identify hepatic activation of PPAR-α as a mechanism underlying glucocorticoid-induced insulin resistance.

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Figure 1: Impaired glucose tolerance and insulin responsiveness in DEX-treated Ppara+/+, but not Ppara−/−, mice.
Figure 2: Ppara and Ppargc1 expression after infusion in DEX-treated Ppara−/−Ldlr−/− mice.
Figure 3: DEX elevates blood pressure and promotes insulin resistance in mice through PPAR-α.
Figure 4: Expression of Ppara and hepatic gluconeogenesis genes.
Figure 5: Gene expression in human hepatocytes, as determined by quantitative RT-PCR.

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Acknowledgements

This study was supported by National Institutes of Health grants HL58427 and AG20091, Clinical Nutrition Research Unit grant DK56341 and Diabetes Research and Training Center grant DK20579. C.B.-M. was supported by an American Diabetes Association–Johnson & Johnson Mentor-Based Postdoctoral Fellowship. We thank E. Bernal-Mizrachi and K.S. Polonsky for suggestions and support.

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Authors and Affiliations

  1. Department of Medicine, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Carlos Bernal-Mizrachi, Sherry Weng, Chu Feng, Brian N Finck, Teresa C Leone, Trey Coleman, Daniel P Kelly & Clay F Semenkovich

  2. Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Carlos Bernal-Mizrachi, Sherry Weng, Chu Feng, Trey Coleman & Clay F Semenkovich

  3. Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Russell H Knutsen & Robert P Mecham

  4. Department of Molecular Biology & Pharmacology Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Daniel P Kelly

  5. Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Brian N Finck, Teresa C Leone, Daniel P Kelly & Clay F Semenkovich

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  1. Carlos Bernal-Mizrachi
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Correspondence to Clay F Semenkovich.

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D.P.K. is a scientific consultant for Merck Research Labs and gives talks supported by Merck. This work was not supported by or related to this affiliation.

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Bernal-Mizrachi, C., Weng, S., Feng, C. et al. Dexamethasone induction of hypertension and diabetes is PPAR-α dependent in LDL receptor–null mice. Nat Med 9, 1069–1075 (2003). https://doi.org/10.1038/nm898

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