Nature Medicine
9, 1069 - 1075 (2003)
Published online: 6 July 2003; | doi:10.1038/nm898
Dexamethasone induction of hypertension and diabetes is PPAR- dependent in LDL receptor−null miceCarlos Bernal-Mizrachi1, 2, Sherry Weng1, 2, Chu Feng1, 2, Brian N Finck1, 5, Russell H Knutsen3, Teresa C Leone1, 5, Trey Coleman1, 2, Robert P Mecham3, Daniel P Kelly1, 4, 5
& Clay F Semenkovich1, 2, 51
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 USA. 2
Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110 USA. 3
Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 USA. 4
Department of Molecular Biology & Pharmacology Washington University School of Medicine, St. Louis, Missouri 63110 USA. 5
Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri 63110 USA.
Correspondence should be addressed to Clay F Semenkovich semenkov@im.wustl.eduHypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator−activated receptor- (PPAR-) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr-/-), with (Ppara+/+) or without (Ppara-/-) PPAR-, 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- 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- agonist Wy14,643 induced PPARA and gluconeogenic gene expression. These results identify hepatic activation of PPAR- as a mechanism underlying glucocorticoid-induced insulin resistance.
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