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Remodeling of White Adipose Tissue after Retinoic Acid Administration in Mice

Laboratory of Molecular Biology, Nutrition and Biotechnology (J.M., J.R., F.F., M.L.B., A.P.), University of the Balearic Islands, 07122 Palma de Mallorca, Spain; and Institute of Normal Human Morphology (I.M., S.C.), Faculty of Medicine, University of Ancona, I-60020 Ancona, Italy

Address all correspondence and requests for reprints to: Dr. M. Luisa Bonet, Laboratori de Biologia Molecular, Nutrició i Biotecnologia, Departament de Biologia Fonamental i Ciències de la Salut, Universitat de les Illes Balears, Carretera Valldemossa Km 7.5, 07122 Palma de Mallorca, Spain. E-mail: luisabonet{at}uib.es.

A reduced brown adipose phenotype in white adipose tissue (WAT) may contribute to obesity and type 2 diabetes in humans. Retinoic acid, the carboxylic form of vitamin A, triggers in rodents a reduction of body weight and adiposity and an increased expression of uncoupling proteins in brown adipose tissue and skeletal muscle. In this study, we investigated possible remodeling effects of all-trans retinoic acid (ATRA) in WAT depots. Changes in the expression of genes related to thermogenesis and fatty acid oxidation and levels of phosphorylated retinoblastoma protein were analyzed in WAT depots of adult NMRI male mice acutely injected with ATRA or vehicle, together with biometric and blood parameters. Body fat loss after ATRA treatment was unaccompanied by any increase in circulating nonesterified fatty acids or ketone bodies and accompanied by increased rectal temperature. The treatment triggered an up-regulation of the mRNA levels of uncoupling proteins 1 and 2, peroxisome proliferator-activated receptor coactivator-1, peroxisome proliferator-activated receptor , muscle- and liver-type carnitine palmitoyltransferase 1, and subunit II of cytochrome oxidase in different WAT depots. Levels of phosphorylated retinoblastoma protein in WAT depots were increased after ATRA treatment. Adipocyte size was reduced, and the number of multilocular adipocytes was increased in inguinal WAT of ATRA-treated mice. The results indicate that ATRA favors the acquisition of brown adipose tissue-like properties in WAT. Understanding the mechanisms and effectors involved in the remodeling of WAT can contribute to new avenues of prevention and treatment of obesity and type 2 diabetes.

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