BMP7 and the regulation of central and peripheral energy balance

DESCRIPTION (provided by applicant): Obesity is currently a worldwide epidemic, therefore preventing and reversing obesity is of utmost importance for the general health of the population. Body weight regulation is maintained through a balance of energy intake versus energy expenditure, and targeting appetite or metabolic pathways via obesity therapeutics is a current goal in obesity research. The brain is the center for control and coordination of body weight. Hypothalamic melanocortin system activation reduces appetite, and also sends signals to the nucleus of the solitary tract (NTS) which activates sympathetic nervous system (SNS) innervation of brown adipose tissue (BAT), leading to increased thermogenesis (energy expenditure). The aim of this proposal is to further investigate a family of molecules recently found to be involved in metabolism. The bone morphogenetic proteins (BMPs) are growth factors, and recent studies have demonstrated roles for the BMPs in metabolism and satiety in lower organisms. Our laboratory has also shown that BMP7 in mice is able to stimulate brown adipocyte differentiation and to induce BAT thermogenesis. Additionally, we have shown that BMP7 and its receptors are expressed in the hypothalamus and BMP7 delivery (either i.c.v. or systemically via adenovirus) produces an anorexigenic effect, at least in part through the hypothalamic mTOR pathway and activation of the melanocortin system. However, much is still unknown about the metabolic and physiological roles of BMP signaling in energy balance. Therefore, the overarching goal of this project is to identify how BMP7 impacts whole body energy balance by affecting appetite pathways and BAT thermogenesis. Thus far, we have found that mice with BMP7 haploinsufficiency (BMP7-/+) on a high fat diet (HFD) are more obese and hyperphagic than littermate controls, with decreased energy expenditure (oxygen consumption/VO2) levels. Therefore, our first objective is to determine the physiological mechanism for BMP7's effects on energy balance, with the hypothesis that BMP7 is regulating the hypothalamic-NTS melanocortin system which regulates both central appetite pathways as well as energy expenditure pathways (via sympathetic innervation of BAT). We have also shown that mice with POMC-neuron (ie: in hypothalamus and NTS/brainstem) deletion of BMPR1a (a BMP7 receptor) exhibit hyperphagia as well as increased energy expenditure and BAT thermogenesis. Therefore our second objective is to determine whether the mechanism for POMC-neuron BMPR1a action is through hypothalamic melanocortin pathway inhibition to induce hyperphagia, and through the NTS-SNS pathways to increase thermogenesis in BAT. These studies will utilize novel mouse models for metabolic studies, including an important model linking central BMP signaling disruption with peripheral energy expenditure effects, and will investigate a novel class of appetite factors: the BMP growth factors. Therefore, the research outlined in this proposal could provide important new findings for the field of obesity research, and potentially lead to development of new obesity therapeutics.