BMP7 and the regulation of central and peripheral energy balance

BMP7与中枢和外周能量平衡的调节

• 批准号: 8202892
• 负责人: Kristy L Townsend
• 金额: $ 5.3万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-07 至 2013-06-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202892
• 关键词: Adenoviruses; Adrenergic Agents; Affect; Agonist; Appetite Depressants; Appetite Regulation; BMP7 gene; Biochemical; Body Weight; Bone Morphogenetic Proteins; Brain; Brain Stem; Brown Fat; Cell Nucleus; Cells; Communication; Complex; Desire for food; Development; Diabetes Mellitus; Diet; Eating; Energy Intake; Energy Metabolism; Epidemic; Equation; Equilibrium; Exhibits; Family; Fatty acid glycerol esters; Functional disorder; Goals; Growth Factor; Homeostasis; Human; Hyperphagia; Hypothalamic structure; Laboratories; Lead; Link; Lower Organism; Manuscripts; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Molecular; Morphogenesis; Mus; Nervous system structure; Neuraxis; Neurons; Neuropeptides; Nucleus solitarius; Obesity; Oxygen Consumption; Pathway interactions; Peripheral; Phenotype; Physiological; Play; Prevention strategy; Regulation; Regulatory Pathway; Research; Role; Satiation; Science; Signal Transduction; Sympathectomy; Sympathetic Nervous System; System; Therapeutic; Thermogenesis; adipocyte differentiation; adrenergic; bone morphogenetic protein receptors; energy balance; human FRAP1 protein; interest; melanocortin receptor; metabolic abnormality assessment; mouse model; nerve supply; novel; population health; prevent; receptor; response

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.

描述（由申请人提供）：肥胖目前是世界范围内的流行病，因此预防和逆转肥胖对于人口的整体健康至关重要。体重调节是通过能量摄入与能量消耗的平衡来维持的，通过肥胖治疗来瞄准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枢。下丘脑黑皮质素系统激活会降低食欲，还会向孤束核 (NTS) 发送信号，激活棕色脂肪组织 (BAT) 的交感神经系统 (SNS) 神经支配，从而导致生热作用（能量消耗）增加。该提案的目的是进一步研究最近发现的参与新陈代谢的分子家族。骨形态发生蛋白 (BMP) 是生长因子，最近的研究证明了 BMP 在低等生物体的新陈代谢和饱腹感中的作用。我们的实验室还表明，小鼠体内的 BMP7 能够刺激棕色脂肪细胞分化并诱导 BAT 产热。此外，我们还表明，BMP7 及其受体在下丘脑中表达，并且 BMP7 递送（静脉注射或通过腺病毒全身给药）会产生厌食作用，至少部分通过下丘脑 mTOR 途径和黑皮质素系统的激活。然而，关于 BMP 信号在能量平衡中的代谢和生理作用仍然未知。因此，该项目的首要目标是确定 BMP7 如何通过影响食欲途径和 BAT 生热作用来影响全身能量平衡。到目前为止，我们发现，采用高脂肪饮食 (HFD) 的 BMP7 单倍体不足 (BMP7-/+) 小鼠比同窝对照小鼠更加肥胖和贪食，并且能量消耗（耗氧量/VO2）水平降低。因此，我们的首要目标是确定 BMP7 对能量平衡影响的生理机制，假设 BMP7 调节下丘脑-NTS 黑皮质素系统，该系统调节中枢食欲途径和能量消耗途径（通过 BAT 的交感神经支配）。我们还发现，POMC 神经元（即：下丘脑和 NTS/脑干）缺失 BMPR1a（BMP7 受体）的小鼠表现出食欲亢进以及能量消耗和 BAT 生热作用增加。因此，我们的第二个目标是确定 POMC 神经元 BMPR1a 作用的机制是否是通过下丘脑黑皮质素通路抑制来诱导食欲亢进，并通过 NTS-SNS 通路来增加 BAT 中的生热作用。这些研究将利用新型小鼠模型进行代谢研究，包括将中枢 BMP 信号干扰与外周能量消耗影响联系起来的重要模型，并将研究一类新型食欲因子：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，并有可能导致新的肥胖疗法的开发。 公共卫生相关性：肥胖目前在世界范围内流行，因此当前的生物医学寻求开发肥胖治疗方法并了解肥胖的病理生理学，以便实施预防策略。该项目利用两种新型小鼠模型来研究 BMP（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。