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 gamma coactivator-1alpha, peroxisome proliferator-activated receptor alpha, 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.

Beyond their classical nutritional roles, nutrients modify gene expression and function in target cells and, by so doing, affect many fundamental biological processes. An emerging example, which is the focus of this review, is the involvement of vitamin A in the regulation of the level and functioning of body fat reserves. Retinoic acid, the carboxylic acid form of vitamin A, is a transcriptional activator of the genes encoding uncoupling proteins, and results in animals indicate that whole body thermogenic capacity is related to the vitamin A status. Retinoic acid also influences adipocyte differentiation and survival, with high doses inhibiting and low doses promoting adipogenesis of preadipose cells in culture. Moreover, vitamin A status can influence the development and function of adipose tissues in whole animals, with a low vitamin A status favouring increased fat deposition.

RIBOT, JOAN, FRANCISCO FELIPE, M. LUISA BONET, AND ANDREU PALOU. Changes of adiposity in response to vitamin A status correlate with changes of PPAR␥2 expression. Obes Res. 2001;9:500 -509. Objective: To gain insight into the in vivo modulation of the expression of the adipogenic transcription factors PPAR␥2, C/EBP␣, and ADD1/SREBP1c by retinoids and its relationship with whole-body adiposity. Research Methods and Procedures: Three-week-old mice were fed with standard chow or a vitamin A-deficient diet for 10 weeks. During the 4 days immediately before they were killed, the animals were treated either with all-trans retinoic acid (tRA; 100 mg/kg per day, subcutaneously) or vehicle. The specific levels of the mRNAs for the three transcription factors were analyzed in epididymal white adipose tissue (eWAT) and inguinal white adipose tissue and in brown adipose tissue (BAT). Other parameters determined were leptin and UCP2 levels in white adipose tissue depots, total cholesterol and triglyceride serum levels, energy intake, body weight, and adiposity. Results: Vitamin A-deficient diet feeding led to a marked increase of adiposity and to a small increase of body weight. Hypertrophy of white adipose tissue depots correlated with enhanced PPAR␥2 expression. Hypertrophy of BAT, in contrast, correlated with a decrease of PPAR␥2 expression that may contribute to the known reduced thermogenic potential of BAT under conditions of vitamin A restriction. Treatment with tRA triggered a reduction of adiposity and body weight that correlated with a down-regulation of PPAR␥2 expression in all adipose tissues. The effects of tRA were more pronounced in eWAT, where C/EBP␣ and ADD1/SREBP1c levels were also reduced. The response to tRA was impaired in the eWAT and BAT of animals fed the vitamin A-deficient diet. Discussion: The results emphasize the importance of retinoids as physiological regulators of adipose tissue development and function in intact animals.

The relationship between interscapular brown adipose tissue (IBAT) thermogenic potential and vitamin A status was investigated by studying the effects of feeding a vitamin A-deficient diet and all-trans retinoic acid (tRA) treatment on body weight and IBAT parameters in mice. Feeding a vitamin A-deficient diet tended to trigger opposite effects to those of tRA treatment, namely increased body weight, IBAT weight, adiposity and leptin mRNA expression, and reduced IBAT thermogenic potential in terms of uncoupling protein 1 (UCP1) mRNA and UCP2 mRNA expression. The results emphasize the importance of retinoids as physiological regulators of brown adipose tissue.