Hypothalamic Bone Morphogenetic Protein Receptor 1A (BMPR1A) Regulates Energy Balance

Energy balance and body weight are regulated by complex processes in the brain, and our understanding of the relevant signaling pathways is still evolving. The main anorectic neurons of the hypothalamus contain pro-opiomelanocortin (POMC). We have previously shown that bone morphogenetic protein 7 (BMP7) acts centrally to reduce appetite. Now we demonstrate that a type 1 BMP receptor, BMPR1A, is co-localized with POMC neurons and ablation of BMPR1A in those neurons results in hyperphagia with a lack of obesity, even on a high-fat diet. This was due to a compensatory increase of BMPR1A expression in non-POMC neurons of the hypothalamus of the knock-out mice, accompanied by an increase in energy expenditure and improved cold-tolerance. Brown adipose tissue (BAT) of knock-out animals showed greater thermogenic capacity and increased sympathetic innervation, and removal of the sympathetic drive to BAT by surgical denervation resulted in hyperphagic weight gain in the knock-out mice. Wild-type mice injected intracerebroventricularly (i.c.v.) with BMP7 displayed an acute increase in energy expenditure and rats injected i.c.v. with BMP7 displayed a specifi c increase in sympathetic nerve activity (SNA) in BAT, along with increased BAT temperature and energy expenditure. In these animals, blockade of type 1 BMP receptor signaling by pre-treatment with a pharmacological inhibitor blunted the ability of BMP7 to increase energy expenditure or BAT SNA. Together, these data demonstrate an important novel role for hypothalamic BMP signaling in the regulation of appetite and activation of brown fat-mediated energy expenditure. Supported By: American Diabetes Association (1-14-JF-55 to K.L.T.)