Effects of fenofibrate on lipid metabolism in adipose tissue of rats Adaliene Versiani Matos Ferreira a , Gleydes Gambogi Parreira b , Allan Green c , Leida Maria Botion a, * a Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG 31270-901, Brazil b Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG 31270-901, Brazil c Bassett Research Institute, Mary Imogene Bassett Hospital, One Atwell Road, Cooperstown, NY 13326, USA Received 27 June 2005; accepted 8 January 2006 Abstract The effect of fenofibrate, a peroxisome proliferator–activated receptor a agonist, on body weight gain and on reduction of adipose tissue pads has been ascribed to increased fat catabolism in liver mainly through the induction of target enzymes involved in hepatic lipid metabolism. The aim of this study was to investigate whether peroxisome proliferator–activated receptor a activation also affects metabolic pathways in adipose tissue of rats treated with fenofibrate (100 mg/kg body weight) for 9 days. Fenofibrate lowered body weight gain and plasma triglyceride, total cholesterol, and high-density lipoprotein cholesterol but had no influence on food intake and on plasma glucose levels. The activity of lipoprotein lipase of treated animals decreased 50% in epididymal, 29% in retroperitoneal, and was not affected in the mesenteric fat pads. In this study, we show a 34% decrease in epididymal adipose tissue de novo lipogenesis by fenofibrate. The results demonstrate that insulin sensitivity of lipolysis is decreased in fenofibrate-treated rats which resulted in 30% higher rate of glycerol release when compared to the control group. These findings suggest that besides its effects on liver, fenofibrate exerts effects on lipid metabolism in adipose tissue which may contribute to decreasing adiposity. D 2006 Elsevier Inc. All rights reserved. 1. Introduction Lipid deposition in adipose tissue is dependent on the availability and uptake of exogenous nonesterified fatty acids (FAs) released from plasma lipoproteins by lipoprotein lipase (LPL) [1] and the rate of de novo synthesis (lipogenesis) of FA within the tissue [2]. The amount of FA released to the bloodstream from stored triglyceride is mainly dependent on the rate of lipolysis, mediated by hormone-sensitive lipase [3]. Lipogenesis and lipoprotein uptake are both stimulated by insulin [4,5], whereas lipolysis is inhibited by insulin and stimulated by cathecol- amines [6]. Several aspects of intracellular lipid and FA metabolism in cells are subjected to transcriptional control by the peroxisome proliferator–activated receptor (PPAR) family. Three receptor subtypes of PPAR termed a , b, and c have been identified [7]. These receptors heterodimerize with the retinoid X receptor and alter the transcription of target genes after binding to peroxisome proliferator response elements located in the promoter region of target genes [8]. The transcriptional activity of PPAR subtypes is enhanced by 2 classes of drugs, fibrates and glitazones. Fibrates and their derivatives constitute a group of hypolipidemic agents that are widely used in the treatment of hypertriglyceridemia and combined hyperlipidemia, being particularly effective in lowering the plasma triglyceride and increasing plasma high-density lipoprotein (HDL) [2,9-12]. The pharmacological actions of fibrates have been found to be mediated through activation of the PPARa [7], leading to expression of genes involved in lipid and lipoprotein metabolism [13]. PPARa is expressed predominantly in liver and, to a lesser extent, in heart and muscle, where it has a crucial role in controlling FA oxidation [14]. It has been reported that fenofibrate can reduce body weight gain in animal models of diabetes [15], obesity [16], and insulin resistance such as fatty fa/fa Zucker rats and high-fat–fed C57B1/6 mice [17]. This effect of fenofibrate on body weight gain and on reduction 0026-0495/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.metabol.2006.01.020 * Corresponding author. Tel.: +55 31 3499 2944; fax: +55 31 3499 2924. E-mail address: botion@icb.ufmg.br (L.M. Botion). Metabolism Clinical and Experimental 55 (2006) 731 – 735 www.elsevier.com/locate/metabol