1530-P: Retinoic Acid Signals in the Hypothalamus Regulate Energy Balance in a Sexually Dimorphic Manner

Abstract

Retinoic acid (RA) is the active metabolite of Vitamin A (Vit-A), and both Vit-A and RA are essential micronutrients for life. Vit-A-deficient mice are leaner than Vit-A-sufficient mice fed with either chow or high-fat-diet (HFD), implying the role of RA in promoting body weight gain. Global loss of key RA synthesis enzyme retinaldehyde dehydrogenase-1 (Aldh1a1) or RA receptor retinoid X receptor gama (RXRγ) both protects mice from diet-induced obesity (DIO). However, the metabolic roles of central RA, especially the endogenously RA synthesized in the hypothalamus, are unclear. Both the RA synthesizing enzymes including Aldh1a1 and RA receptors including RXRγ and retinoic acid receptor beta (RARβ), are accumulated in the hypothalamus. We found that loss of RXRγ or RARβ in pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of hypothalamus (ARH) produced lean phenotypes in a sexually dimorphic manner. In particular, loss of RXRγ in POMC neurons reduce body weight and food intake only in chow-fed female mice, but not in male mice; meanwhile, loss of RARβ in in POMC neurons reduce body weight in both sexes, with reduced food intake in male mice but not in female mice. Independent of body weight, glucose tolerance and insulin tolerance were not changed by POMC specific deficiency of either RXRγ or RARβ in either sex. Since RA can bind to both RXRγ and RARβ, and RA can be locally synthesized in the hypothalamus using Vit-A metabolites as substrates, these results support that RA acts on RXRγ and RARβ in POMC neurons to regulate energy balance in a sexually dimorphic manner. These studies will advance our understanding about the physiology of body weight/glucose balance regulated by RA and RXR or RAR complexes, which will facilitate the characterization of the current RA or RXR-based therapies and provide novel targets for anti-obesity/diabetes therapies. Disclosure M.Yu: None. Y.Yang: None. Y.He: None. J.Bean: None. H.Liu: None. C.Wang: None.