Hypothalamic autophagy and metabolic regulation in aging

衰老过程中的下丘脑自噬和代谢调节

• 批准号: 9246425
• 负责人: Rajat Singh
• 金额: $ 31.43万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246425
• 关键词: Ablation; Address; Adipocytes; Adverse effects; Affect; Age; Age-Years; Aging; Appetite Regulation; Appetite Stimulants; Autophagocytosis; Biochemical; Biochemical Genetics; Biological Models; Caloric Restriction; Cell Line; Central obesity; Cognition; Data; Development; Dietary Intervention; Eating; Energy Metabolism; Equilibrium; Event; Exhibits; Failure; Fatty acid glycerol esters; Food; Food Energy; Functional disorder; Genes; Genetic; Glucose; Glucose Intolerance; Goals; Health; Hepatic; Homeostasis; Hormonal; Hyperlipidemia; Hypertension; Hypothalamic structure; Image; Impairment; Insulin Resistance; Intervention; Knockout Mice; Link; Lipids; Longevity; Lysosomes; Measures; Mediating; Melanocyte stimulating hormone; Metabolic; Metabolic syndrome; Motor Activity; Mus; Neurons; Neuropeptides; Nutrient; Nutritional; Obesity; Organ; Organelles; Organism; Overnutrition; Peptides; Peripheral; Population; Pro-Opiomelanocortin; Process; Production; Proteins; Publishing; Quality Control; Quality of life; Regulation; Rodent; Role; Signal Transduction; Starvation; Stress; Therapeutic; Visceral; Vision; age effect; aged; aging population; base; blood glucose regulation; cerebrovascular health; cohort; energy balance; feeding; feeding schedule; global health; improved; insulin sensitivity; middle age; novel; prevent; public health relevance; response; restoration; tumor; young adult

DESCRIPTION (provided by applicant): The metabolic syndrome is characterized by visceral obesity, hypertension, hyperlipidemia, and insulin resistance. Whole body energy balance is maintained through the integration of nutritional and hormonal information by two distinct neuronal populations in the mediobasal hypothalamus, the agouti-related peptide (AgRP) and the proopiomelanocortin (POMC) neurons. The hypothalamic POMC neurons express POMC that is processed to generate �-melanocyte stimulating hormone (�-MSH), which promotes energy expenditure. Macroautophagy (MA) is an essential mechanism that maintains cellular homeostasis by degrading proteins and organelles in lysosomes. Our published results have shown a role for MA in hypothalamic AgRP neurons in control of food intake. We have found that MA proteins are required for POMC processing and �-MSH production as rodents lacking MA in hypothalamic POMC neurons display reduced �-MSH, increased adiposity and glucose intolerance. Decreased MA activity has been described in different organs in old organisms, and we have now demonstrated a similar decrease in hypothalamic MA with age. The role of MA in hypothalamic �-MSH production, and the mechanisms that reduce hypothalamic MA during aging are unknown. The overall goal of this proposal is to elucidate the contribution of failure of hypothalamic MA with age to the metabolic syndrome of aging. To that purpose we will: 1) determine whether nutrient, and hormonal activation of MA in POMC neurons mechanistically links �-MSH production to peripheral energy expenditure, 2) characterize the neuron-intrinsic mechanisms that decrease MA in hypothalamic POMC neurons with age and in response to high fat feeding, and 3) examine whether restoration of hypothalamic MA using a novel scheduled-feeding intervention reverses or prevents the development of the metabolic syndrome of aging. These studies will be performed in primary hypothalamic neurons, hypothalamic cell lines, and in cohorts of different age control mice or those with the hypothalamic POMC-neuron specific ablation of the MA gene ATG7. Significance: The metabolic syndrome is a significant global health problem that affects greater than 44% of the U.S. population aged more than 50 years. The metabolic syndrome affects health span in the aging population through one of many adverse effects on cardio- and cerebrovascular health, locomotor activity, vision and cognition, as well as on the development of tumors. The current proposal will delineate a novel role for MA in hypothalamic regulation of energy homeostasis, setting the basis for therapeutic modulation of hypothalamic MA in preventing or treating the metabolic syndrome of aging, and in this way improving the quality of life and health-span in the aged.

描述（申请人提供）：代谢综合征的特征是内脏肥胖、高血压、高脂血症和胰岛素抵抗。下丘脑中部的两个不同的神经元群，即刺鼠相关肽 (AgRP) 和阿片黑皮素原 (POMC) 神经元，通过整合营养和激素信息来维持全身能量平衡。下丘脑 POMC 神经元表达 POMC，经过处理后可产生 β-促黑素细胞激素 (β-MSH)，从而促进能量消耗。巨自噬（MA）是通过降解溶酶体中的蛋白质和细胞器来维持细胞稳态的重要机制。我们发表的结果表明 MA 在下丘脑 AgRP 神经元中控制食物摄入的作用。我们发现 MA 蛋白是 POMC 加工和 β-MSH 产生所必需的，因为下丘脑 POMC 神经元中缺乏 MA 的啮齿动物表现出 β-MSH 减少、肥胖和葡萄糖不耐受增加。在老年生物体的不同器官中，MA 活性降低已被描述，我们现在已经证明，随着年龄的增长，下丘脑 MA 也出现类似的降低。 MA 在下丘脑 β-MSH 产生中的作用以及衰老过程中下丘脑 MA 减少的机制尚不清楚。该提案的总体目标是阐明失败的贡献 下丘脑MA随着年龄的增长而出现衰老代谢综合征。为此，我们将：1) 确定 POMC 神经元中 MA 的营养和激素激活是否在机制上将 β-MSH 产生与外周能量消耗联系起来，2) 描述下丘脑 POMC 神经元中 MA 随着年龄的增长和对高脂肪喂养的反应而减少的神经元内在机制，以及 3) 检查是否使用新型计划喂养干预来恢复下丘脑 MA 逆转或预防衰老代谢综合征的发展。这些研究将在原代下丘脑神经元、下丘脑细胞系以及不同年龄对照小鼠或下丘脑 POMC 神经元 MA 基因 ATG7 特异性消融的小鼠群体中进行。意义：代谢综合征是一个重大的全球健康问题，影响超过 44% 的美国 50 岁以上人口。代谢综合征通过对心脑血管健康、运动活动、视力和认知以及肿瘤的发展产生多种不利影响之一，影响老年人的健康寿命。目前的提案将描述 MA 在下丘脑能量稳态调节中的新作用，为下丘脑 MA 在预防或治疗衰老代谢综合征中的治疗调节奠定基础，从而改善老年人的生活质量和健康寿命。