Differential effects of retinoic acid on uncoupling protein-1 and leptin gene expression

Abstract

All-trans-retinoic acid (RA), one of the active metabolites of vitamin A, can increase the expression of uncoupling protein-1 (UCP1) gene. To determine whether RA stimulates brown adipose tissue (BAT) thermogenesis and modulates leptin gene expression in vivo, 6-month-old, vitamin-A sufficient, F344 BN rats were administered a single dose of RA (7·5 mg/kg, i.p.) or the 3 -adrenergic receptor ( 3 AR) specific agonist, CGP 12177 (0·75 mg/ kg). Levels of UCP1 mRNA in BAT and leptin mRNA in perirenal white adipose tissue (WAT) were examined 5 h after treatment. mRNA levels of lipoprotein lipase (LPL) were also examined in BAT and perirenal WAT. Administration of CGP 12177 caused the expected increase in UCP1 mRNA levels. RA treatment also significantly increased UCP1 mRNA levels but to a lesser extent than CGP 12177. In contrast, there was no acute effect of RA on whole body oxygen consumption, one measure of BAT thermogenesis. Both CGP 12177 and RA treatment decreased levels of leptin mRNA to a similar extent. RA treatment had no effect on mRNA levels of LPL in BAT or perirenal WAT. There were no changes in total DNA content, total protein content, or in the levels of -actin mRNA in either BAT or perirenal WAT upon administration of RA or CGP 12177. Thus, the acute effects of RA paralleled the effects of the 3 AR specific agonist, CGP 12177, on UCP1 and leptin gene expression. This involvement of RA in positive regulation of UCP1 mRNA and negative regulation of leptin mRNA suggests a contrasting role for RA in energy homeostasis.

Up-regulation of muscle uncoupling protein 3 gene expression in mice following high fat diet, dietary vitamin A supplementation and acute retinoic acid-treatment

“…43 In the last years, it has become increasingly clear that RA is a modulator of fat metabolism that promotes fat mobilization (and=or apoptosis) in vivo and the transformation of mature adipocytes into cells less capable to store triglycerides and more capable of using fatty acids. Mice acutely treated with RA lose body weight and adiposity 22,28,29 and, overall, the effects of acute RA-treatment on the expression of UCPs -the previously reported induction of BAT UCP1 and UCP2 levels 22,27,28 and the induction of muscle UCP3 reported here -fit well in a framework of enhanced fat metabolism triggered by RA. In this framework, RA induction of UCPs may serve to facilitate the handling of lipids as a fuel, either for heat production or ATP production.…”

“…In fact, studies in humans under high fat diets showed increases of fat oxidation and UCP3 expression in muscle that were not accompanied by increases of circulating NEFA levels. 47,51 Lower levels of adipose leptin mRNA in B6 mice fed vitamin A-supplemented diets is in agreement with downregulation of adipose leptin mRNA levels following acute RA-treatment in rats and mice 27,28 and reduction of circulating leptin levels following dietary vitamin A supplementation in rats. 30 Our results further suggest that retinoids may by themselves exert an inhibitory effect on leptin expression that is not secondary to a reduction of fat content, because the depressed adipose leptin mRNA levels found did not correlate with comparable reductions of the adipose depots mass.…”

“…20 On the other hand, retinoic acid (RA), the carboxylic acid form of vitamin A and a well-known modulator of gene transcription, has been shown to up-regulate the expression of the UCPs in cell model systems, 21 -25 an effect that, in the case of UCP1, has also been demonstrated for certain pro-vitamin A carotenoids. 26 Up-regulation of BAT UCP1 22,27,28 and UCP2 28 expression was also reported after acute RA-treatment in intact rodents, where it correlated with a significant reduction of body weight and body adiposity. 22,28,29 Moreover, mice fed a vitamin A-deficient diet had reduced levels of expression of UCP1 and UCP2 in BAT, increased levels of expression of adipogenic transcription factors in white fat depots, and a higher adiposity and body weight than control mice, 28,29 suggesting that the vitamin A status can affect both the thermogenic and the adipogenic capacity of rodents.…”

Opposite effects of feeding a vitamin A-deficient diet and retinoic acid treatment on brown adipose tissue uncoupling protein 1 (UCP1), UCP2 and leptin expression

“…We found inhibition of leptin mRNA expression in the IBAT of tRA-treated mice, whether fed standard chow or vitamin A-deficient diet; the same effect was reported in the perirenal white fat of vitamin A-sufficient rats acutely treated with RA (Kumar & Scarpace 1998) or chronically fed a retinol-supplemented diet (Kumar et al 1999). Considering the marked reduction of IBAT adiposity brought about by tRA treatment (Fig.…”

Retinoic acid and vitamin D(3) powerfully inhibit in vitro leptin secretion by human adipose tissue

“…Adipose tissue have long been recognized as a potential site for the action of RAs, and the two retinoid receptors, RAR and RXR, are both expressed in adipose tissue (Villarroya et al 1999). All-trans-RA has been recently described as new regulator of UCP1 gene and ob gene in rat perirenal white adipose tissue (Kumar & Scarpace 1998), but there are presently no data available regarding its action on the in vitro leptin secretion by human adipose tissue.…”