Peroxisome Proliferator-Activated Receptors γ and α Mediate in Vivo Regulation of Uncoupling Protein (UCP-1, UCP-2, UCP-3) Gene Expression (original) (raw)

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1Departments of Molecular Endocrinology (L.J.K., G.M.T., T.W.D., J.V., M.S.W., D.E.M.), Merck Research Laboratories, Rahway, New Jersey 07065;

*Address all correspondence and requests for reprints to: Dr. Linda Kelly, Merck Research Laboratories, 80W-207 P.O. Box 2000, Rahway, New Jersey 07065.

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2Departments of Molecular Pharmacology and Biochemistry (P.P.V., M.R.C., M.A.C.), Merck Research Laboratories, Rahway, New Jersey 07065;

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1Departments of Molecular Endocrinology (L.J.K., G.M.T., T.W.D., J.V., M.S.W., D.E.M.), Merck Research Laboratories, Rahway, New Jersey 07065;

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2Departments of Molecular Pharmacology and Biochemistry (P.P.V., M.R.C., M.A.C.), Merck Research Laboratories, Rahway, New Jersey 07065;

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1Departments of Molecular Endocrinology (L.J.K., G.M.T., T.W.D., J.V., M.S.W., D.E.M.), Merck Research Laboratories, Rahway, New Jersey 07065;

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1Departments of Molecular Endocrinology (L.J.K., G.M.T., T.W.D., J.V., M.S.W., D.E.M.), Merck Research Laboratories, Rahway, New Jersey 07065;

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1Departments of Molecular Endocrinology (L.J.K., G.M.T., T.W.D., J.V., M.S.W., D.E.M.), Merck Research Laboratories, Rahway, New Jersey 07065;

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3Departments of Cellular and Molecular Pharmacology (R.M., M.J.F.), Merck Research Laboratories, Rahway, New Jersey 07065;

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3Departments of Cellular and Molecular Pharmacology (R.M., M.J.F.), Merck Research Laboratories, Rahway, New Jersey 07065;

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4Department of Safety Assessment (M.W.C.), Merck Research Laboratories, West Point, Pennsylvania 19486

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Published:

01 December 1998

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Linda J. Kelly, Pasquale P. Vicario, G. Marie Thompson, Mari R. Candelore, Thomas W. Doebber, John Ventre, Margaret S. Wu, Roger Meurer, Michael J. Forrest, Michael W. Conner, Margaret A. Cascieri, David E. Moller, Peroxisome Proliferator-Activated Receptors γ and α Mediate in Vivo Regulation of Uncoupling Protein (UCP-1, UCP-2, UCP-3) Gene Expression, Endocrinology, Volume 139, Issue 12, 1 December 1998, Pages 4920–4927, https://doi.org/10.1210/endo.139.12.6384
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Abstract

A role for peroxisome proliferator-activated receptors, PPARγ and PPARα, as regulators of energy homeostasis and lipid metabolism, has been suggested. Recently, three distinct uncoupling protein isoforms, UCP-1, UCP-2, and UCP-3, have also been identified and implicated as mediators of thermogenesis. Here, we examined whether in vivo PPARγ or PPARα activation regulates the expression of all three UCP isoforms. Rats or lean and db/db mice were treated with PPARγ [thiazolidinedione (TZD)] or PPARα (WY-14643) agonists, followed by measurement of messenger RNAs (mRNAs) for UCP-1, UCP-2, and UCP-3 in selected tissues where they are expressed. TZD treatment (AD 5075 at 5 mg/kg·day) of rats (14 days) increased brown adipose tissue (BAT) depot size and induced the expression of each UCP mRNA (3× control levels for UCP-1 and UCP-2, 2.5× control for UCP-3). In contrast, UCP-2 and UCP-3 mRNA levels were not affected in white adipose tissue or skeletal muscle. Chronic (30 days) low-dose (0.3 mg/kg·day) TZD treatment induced UCP-1 mRNA and protein in BAT (2.5× control). In contrast, chronic TZD treatment (30 mg/kg·day) suppressed UCP-1 mRNA (>80%) and protein (50%) expression in BAT. This was associated with further induction of UCP-2 expression (>10-fold) and an increase in the size of lipid vacuoles, a decrease in the number of lipid vacuoles in each adipocyte, and an increase in the size of the adipocytes. TZD treatment of db/db mice (BRL 49653 at 10 mg/kg·day for 10 days) also induced UCP-1 and UCP-3 (but not UCP-2) expression in BAT. PPARα is present in BAT, as well as liver. Treatment of rats or db/db mice with WY-14643 did not affect expression of UCP-1, -2, or -3 in BAT. Hepatic UCP-2 mRNA was increased (4× control level) in db/db and lean mice, although this effect was not observed in rats. Thus, in vivo PPARγ activation can induce expression of UCP-1, -2, and -3 in BAT; whereas chronic-intense PPARγ activation may cause BAT to assume white adipose tissue-like phenotype with increased UCP-2 levels. PPARα activation in mice is sufficient to induce liver UCP-2 expression.

Copyright © 1998 by The Endocrine Society

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