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Peroxisome Proliferator-Activated Receptor--Mediated Positive Energy Balance in the Rat Is Associated with Reduced Sympathetic Drive to Adipose Tissues and Thyroid Status

Laval Hospital Research Center (W.T.F., M.L., M.B., C.M., R.G.D., D.R., Y.D.), Faculty of Medicine, Laval University, Quebec, Canada G1V 4G5; Department of Biochemistry (S.O.), Medical Faculty of Istanbul, Istanbul University, Istanbul 34452, Turkey; Geriatrics Research (S.O., S.D., W.A.B.), Education, and Clinical Center, Veterans Affairs Medical Center, St. Louis, St. Louis, Missouri 63106; Division of Geriatrics (W.A.B.), Department of Internal Medicine, St. Louis University School of Medicine, St. Louis, Missouri 63104; Laboratory of Pharmacology and Chemistry (D.S.M.), National Institute of Environmental Health Science, National Institutes of Health, Research Triangle Park, North Carolina 27709; and Biology Department (M.N.B., N.A.B., T.J.B.), Georgia State University, Atlanta, Georgia 30302

Address all correspondence and requests for reprints to: Dr. Yves Deshaies, Faculty of Medicine, Laval University, Laval Hospital Research Centre, Laval Hospital–d’Youville Y3110, 2725 Chemin Sainte-Foy, Quebec, Canada G1V 4G5. E-mail: yves.deshaies{at}phs.ulaval.ca.

Peroxisome proliferator-activated receptor- (PPAR) activation up-regulates thermogenesis-related genes in rodent white and brown adipose tissues (WAT and BAT) without increasing whole-body energy expenditure. We tested here whether such dissociation is the result of a negative modulation of sympathetic activity to WAT and BAT and thyroid axis components by PPAR activation. Administration of the PPAR agonist rosiglitazone (15 mg/kg·d) for 7 d to male Sprague Dawley rats increased food intake (10%), feed efficiency (31%), weight gain (45%), spontaneous motor activity (60%), and BAT and WAT mass and reduced whole-body oxygen consumption. Consistent with an anabolic setting, rosiglitazone markedly reduced sympathetic activity to BAT and WAT (>50%) and thyroid status as evidenced by reduced levels of plasma thyroid hormones (T₄ and T₃) and mRNA levels of BAT and liver T₃-generating enzymes iodothyronine type 2 (–40%) and type 1 (–32%) deiodinases, respectively. Rosiglitazone also decreased mRNA levels of the thyroid hormone receptor (THR) isoforms 1 (–34%) and β (–66%) in BAT and isoforms 1 (–20%) and 2 (–47%) in retroperitoneal WAT. These metabolic effects were associated with a reduction in mRNA levels of the pro-energy expenditure peptides CRH and CART in specific hypothalamic nuclei. A direct central action of rosiglitazone is, however, unlikely based on its low brain uptake and lack of metabolic effects of intracerebroventricular administration. In conclusion, a reduction in BAT sympathetic activity and thyroid status appears to, at least partly, explain the PPAR-induced reduction in energy expenditure and the fact that up-regulation of thermogenic gene expression does not translate into functional stimulation of whole-body thermogenesis in vivo.

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