The Central Melanocortin System and Regulation of Energy Balance

中枢黑皮质素系统和能量平衡的调节

• 批准号: 8033115
• 负责人: Sharon L. Wardlaw
• 金额: $ 33.53万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033115
• 关键词: ART protein; Affect; Biological; Biological Assay; Body Weight; Brain; C-terminal; Diabetes Mellitus; Diet; Eating; Energy Metabolism; Enzymes; Fatty Liver; Fatty acid glycerol esters; Genetic Models; Hepatic; Hormonal; Human; Hypothalamic structure; In Vitro; Injection of therapeutic agent; Mus; Mutation; N-terminal; Names; Neurons; Nutrient; Obesity; Peptides; Peripheral; Play; Prevalence; Prevention; Principal Investigator; Pro-Opiomelanocortin; Process; Proprotein Convertase 1; Protocols documentation; Regulation; Research; Rodent Model; Role; Signal Transduction; System; Transgenic Mice; design; energy balance; feeding; glucose metabolism; improved; in vivo; melanocortin receptor; novel; nutrient metabolism; overexpression; oxidation; programs; public health relevance; response; small molecule

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand how the brain senses levels of peripheral energy stores and integrates these signals to maintain energy balance. Studies will focus on the central melanocortin system in rodent models and on the mechanisms by which it can sense and integrate a variety of nutrient, hormonal and neuronal signals to regulate food intake, energy expenditure and nutrient metabolism. This system consists of proopiomelanocortin (POMC) and the POMC-derived MSH peptides together with agouti related protein (AGRP) which is a potent antagonist of the MSH peptides at specific melanocortin receptors (MC3/4-R). a-MSH inhibits feeding and stimulates energy expenditure while AGRP exerts opposite effects. Aim 1 will use recently generated transgenic mice that overexpress a-MSH and g- MSH (Tg-MSH) to study the role of the melanocortin system in modulating responses to energy excess on a high fat diet and to characterize underlying mechanisms with a focus on energy expenditure, fuel oxidation, sympathetic activity and hepatic steatosis. Tg-MSH mice demonstrate reduced body weight, adiposity and hepatic fat accumulation (without changes in food intake) and improved glucose metabolism, particularly in the setting of diet-induced obesity. The role of AGRP will be similarly studied in Aim 2 using a genetic model of Agrp deletion and a novel, potent, small molecule AGRP antagonist. Aims 3 & 4 will focus on the regulation of POMC and AGRP peptide processing in the hypothalamus in vivo and in vitro with respect to energy balance. This is an important consideration because POMC is processed to a number of peptides with different and even opposing biological activities. The ability of these peptide products to interact and regulate energy balance will be studied in parallel using icv injection protocols. AGRP is also processed by PC1 to a biologically active C-terminal fragment but little is known about the regulation of processing or about the N-terminal peptides that are produced that may also affect energy balance. AGRP processing will be characterized using novel assays and the effects of these processed peptides on energy balance will then be studied. This proposal is highly relevant to human energy balance as mutations in POMC, POMC processing enzymes and in the MC4-R have all been associated with human obesity and there are many parallels with rodent models of melanocortin deficiency. PUBLIC HEALTH RELEVANCE: The increasing prevalence of obesity and diabetes makes it imperative to understand the mechanisms by which the brain regulates energy balance in order to design more effective prevention and treatment options. This proposal will use rodent models to study the brain melanocortin system which plays a key role in regulating energy balance. This system consists of proopiomelanocortin (POMC) and the POMC-derived MSH peptides together with agouti related protein (AGRP) which is a potent antagonist of the MSH peptides at specific melanocortin receptors (MC3/4-R). ?-MSH inhibits feeding and stimulates energy expenditure while AGRP exerts opposite effects. This proposal is highly relevant to human energy balance as mutations in POMC, POMC processing enzymes and in the MC4-R have all been associated with human obesity and there are many parallels with rodent models of melanocortin deficiency.

描述（由申请人提供）：该提案的长期目标是了解大脑如何感知周围能量存储的水平并整合这些信号以维持能量平衡。研究将重点关注啮齿动物模型中的中枢黑皮质素系统及其感知和整合各种营养、激素和神经元信号以调节食物摄入、能量消耗和营养代谢的机制。该系统由阿片黑皮质素原 (POMC) 和 POMC 衍生的 MSH 肽以及刺鼠相关蛋白 (AGRP) 组成，AGRP 是 MSH 肽在特定黑皮质素受体 (MC3/4-R) 上的有效拮抗剂。 a-MSH 抑制进食并刺激能量消耗，而 AGRP 则发挥相反的作用。目标 1 将使用最近生成的过度表达 a-MSH 和 g-MSH (Tg-MSH) 的转基因小鼠来研究黑皮质素系统在调节高脂肪饮食能量过剩反应中的作用，并表征潜在机制，重点是能量消耗、燃料氧化、交感神经活动和肝脂肪变性。 Tg-MSH 小鼠表现出体重减轻、肥胖和肝脏脂肪积累减少（食物摄入量不变）以及葡萄糖代谢改善，特别是在饮食引起的肥胖情况下。 AGRP 的作用将在目标 2 中使用 Agrp 缺失的遗传模型和新型、有效的小分子 AGRP 拮抗剂进行类似的研究。目标 3 和 4 将重点关注体内和体外下丘脑 POMC 和 AGRP 肽加工在能量平衡方面的调节。这是一个重要的考虑因素，因为 POMC 被加工成许多具有不同甚至相反生物活性的肽。这些肽产品相互作用和调节能量平衡的能力将使用 ICV 注射方案并行研究。 AGRP 也被 PC1 加工成具有生物活性的 C 端片段，但对于加工的调节或产生的 N 端肽（也可能影响能量平衡）知之甚少。 AGRP 加工将使用新的测定方法进行表征，然后研究这些加工过的肽对能量平衡的影响。该提议与人类能量平衡高度相关，因为 POMC、POMC 加工酶和 MC4-R 的突变都与人类肥胖有关，并且与黑皮质素缺乏的啮齿动物模型有许多相似之处。 公共健康相关性：肥胖和糖尿病的患病率不断增加，因此必须了解大脑调节能量平衡的机制，以便设计更有效的预防和治疗方案。该提案将利用啮齿动物模型来研究大脑黑皮质素系统，该系统在调节能量平衡中发挥着关键作用。该系统由阿片黑皮质素原 (POMC) 和 POMC 衍生的 MSH 肽以及刺鼠相关蛋白 (AGRP) 组成，AGRP 是 MSH 肽在特定黑皮质素受体 (MC3/4-R) 上的有效拮抗剂。 α-MSH 抑制摄食并刺激能量消耗，而 AGRP 则发挥相反的作用。该提议与人类能量平衡高度相关，因为 POMC、POMC 加工酶和 MC4-R 的突变都与人类肥胖有关，并且与黑皮质素缺乏的啮齿动物模型有许多相似之处。