BMP7 and the regulation of central and peripheral energy balance

描述（由申请人提供）：肥胖症目前是一种世界性流行病，因此预防和逆转肥胖症对人群的总体健康至关重要。通过能量摄入与能量消耗的平衡来维持体重调节，并且通过肥胖治疗靶向食欲或代谢途径是肥胖研究的当前目标。大脑是控制和协调体重的中心。下丘脑黑皮质素系统激活降低食欲，并且还向孤束核（NTS）发送信号，其激活棕色脂肪组织（BAT）的交感神经系统（SNS）神经支配，导致产热（能量消耗）增加。这项建议的目的是进一步研究最近发现的参与代谢的分子家族。骨形态发生蛋白（BMPs）是一种生长因子，最近的研究表明BMPs在低等生物的代谢和饱腹感中起作用。我们的实验室还表明，小鼠中的BMP 7能够刺激棕色脂肪细胞分化并诱导BAT产热。此外，我们已经表明BMP 7及其受体在下丘脑中表达，并且BMP 7递送（i. c. v.或通过腺病毒全身递送）至少部分地通过下丘脑mTOR途径和黑皮质素系统的激活产生促凋亡作用。然而，关于BMP信号在能量平衡中的代谢和生理作用仍然是未知的。因此，该项目的总体目标是确定BMP 7如何通过影响食欲途径和BAT产热来影响全身能量平衡。到目前为止，我们已经发现，与同窝对照组相比，高脂肪饮食（HFD）的BMP 7单倍不足（BMP 7-/+）小鼠更肥胖和贪食，具有降低的能量消耗（耗氧量/VO 2）水平。因此，我们的第一个目标是确定BMP 7对能量平衡的影响的生理机制，假设BMP 7调节下丘脑-NTS黑皮质素系统，该系统调节中枢食欲途径以及能量消耗途径（通过BAT的交感神经支配）。我们还表明，POMC神经元（即：在下丘脑和NTS/脑干）缺失BMPR 1a（一种BMP 7受体）的小鼠表现出摄食过多以及能量消耗和BAT产热增加。因此，我们的第二个目标是确定POMC-神经元BMPR 1a作用的机制是否是通过下丘脑黑皮质素途径抑制诱导摄食过多，以及通过NTS-SNS途径增加BAT中的产热。这些研究将利用新的小鼠模型进行代谢研究，包括一个重要的模型连接中央BMP信号中断与外周能量消耗的影响，并将调查一类新的食欲因子：BMP生长因子。因此，该提案中概述的研究可以为肥胖研究领域提供重要的新发现，并可能导致新的肥胖治疗方法的开发。 公共卫生相关性：肥胖症目前在世界范围内流行，因此目前的生物医学科学寻求开发肥胖症治疗方法并了解肥胖症的病理生理学，以便实施预防策略。本项目利用两种新型小鼠模型来研究骨形态发生蛋白（BMPs），一种生长因子家族，在调节体重稳态的神经系统和棕色脂肪组织途径中的作用。

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. PUBLIC HEALTH RELEVANCE: Obesity is currently epidemic worldwide, therefore current biomedical science seeks to develop obesity therapeutics and to understand the pathophysiology of obesity in order to implement prevention strategies. This project utilizes two novel mouse models to investigate the role of the BMPs, a family of growth factors, in both nervous system and brown adipose tissue pathways regulating body weight homeostasis.