Interactions of Leptin and the Melanocortin System

瘦素和黑皮质素系统的相互作用

• 批准号: 10216246
• 负责人: JOEL K. ELMQUIST
• 金额: $ 41.81万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216246
• 关键词: ADRA2A gene; Acute; Adipocytes; Adipose tissue; Adrenergic Receptor; Adult; Automobile Driving; Behavioral; Blood; Body Weight; Body fat; Brain; Complex; Cues; Data; Development; Diabetes Mellitus; Disease; Eating; Endocrine; Energy Metabolism; Exposure to; Fasting; Fatty acid glycerol esters; Food Energy; Functional disorder; Genetically Engineered Mouse; Glucose; Hand; Hepatic; Homeostasis; Hypothalamic structure; Impairment; Incidence; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Mediating; Metabolic; Metabolism; Modeling; Molecular; Mus; Nervous system structure; Neuraxis; Neurons; Neurosecretory Systems; Nutritional status; Obesity; Pathway interactions; Play; Pro-Opiomelanocortin; Process; Production; Regulation; Role; Signal Transduction; Surface; Sympathetic Nervous System; System; Testing; Tissues; Visceral; base; blood glucose regulation; designer receptors exclusively activated by designer drugs; diabetes mellitus therapy; energy balance; falls; fatty acid oxidation; feeding; genetic manipulation; glucose metabolism; glucose production; insulin sensitivity; leptin receptor; lipid biosynthesis; liver development; liver function; mouse model; prenatal; receptor; targeted treatment

Abstract The increasing rates of obesity and diabetes highlight the need to understand the brain circuits and cellular mechanisms regulating energy balance and glucose homeostasis. Prominent among these is the central leptin- melanocortin system, which includes the pro-opiomelanocortin (POMC) neurons, subsets of which express leptin receptors (LEPRs). Understanding how leptin differentially regulates energy balance versus glucose homeostasis is key for the development of anti-obesity and anti-diabetes therapies. Early observations based on prenatal genetic manipulations led to the widely-held model that LEPR-expressing POMC neurons mediated the metabolic actions of leptin, however, evidence now suggests that these pathways are more complex than originally anticipated. The current application extends our early developmental models by directly testing the role of leptin action in adult melanocortin neurons in regulating glucose metabolism and responding to dynamic challenges, including fasting and cold exposure. We also have in hand a model in which liver insulin resistance can be induced in a temporal manner, allowing us to investigate the role of the leptin- melanocortin pathway in its development. These studies will broaden our understanding of the functional mechanism by which the leptin-melanocortin system regulates endocrine, autonomic, and behavioral functions, particularly at the level of adipose tissues and liver.

摘要 肥胖症和糖尿病发病率的增加突出了了解大脑回路和细胞的必要性。 调节能量平衡和葡萄糖稳态的机制。其中最突出的是中央瘦素- 黑皮质素系统，其包括阿黑皮素原（POMC）神经元，其子集表达 瘦素受体（LEPRs）。了解瘦素与葡萄糖如何不同地调节能量平衡 体内平衡是开发抗肥胖和抗糖尿病疗法的关键。早期的观察基于 产前基因操作导致了广泛持有的模型，LEPR表达POMC神经元 然而，现在的证据表明，这些途径更多的是 比原先预期的复杂。目前的应用程序扩展了我们的早期发展模式，直接 在成年黑皮质素神经元中测试瘦素作用在调节葡萄糖代谢和应答中的作用 动态挑战，包括禁食和寒冷暴露。我们手头也有一个模型， 胰岛素抵抗可以以时间的方式诱导，这使我们能够研究瘦素的作用， melanocortin pathway在其发展过程中这些研究将拓宽我们对功能性 瘦素-黑皮质素系统调节内分泌、自主神经和行为功能的机制， 特别是在脂肪组织和肝脏的水平。