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: 9036919
• 负责人: Rajat Singh
• 金额: $ 34.24万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036919
• 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; Cardiovascular system; 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; 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; 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（由适用提供）：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。通过在中质下丘脑，与Agouti相关的肽（AGRP）和propiomelanocortin（POMC）神经元中的两个不同的神经元种群中，通过营养和马的信息整合营养和马的信息来维持全身能量平衡。下丘脑POMC神经元表达pOMC，该pomc被处理以产生`` - 甲状腺细胞刺激的马酮（� -MSH），从而促进能量消耗。大量噬菌体（MA）是一种基本机制，可以通过降解溶酶体中的蛋白质和细胞器来维持细胞稳态。我们发表的结果表明，MA在下丘脑AGRP神经元中的作用在控制食物摄入量中。我们发现，由于下丘脑POMC神经元中缺少MA的啮齿动物的啮齿动物的表现降低了 - MSH，肥胖和葡萄糖intlerance所必需的MA蛋白是POMC加工和MSH产生所必需的。在旧生物体的不同器官中描述了MA活性的降低，我们现在显示出下丘脑MA随着年龄的增长的类似下降。 MA在下丘脑中的作用 - MSH的产生以及减少下丘脑MA在衰老过程中的机制尚不清楚。该提议的总体目标是阐明失败的贡献 下丘脑MA随年龄至衰老的代谢综合征。为此，我们将：1）确定POMC神经元中MA的养分和激素激活机械上是否将MSH的生产与周围能量支出联系起来，2）2）将MA的神经内在机制表征为减少MA中的MA在下丘脑神经元中降低的MA中的MA在下丘脑神经元与高脂肪的效果相关的效果，并且是否恢复了效果。干预逆转或防止衰老的代谢综合征的发展。这些研究将在原发性下丘脑神经元，下丘脑细胞系以及不同年龄对照小鼠的同类中或具有下丘脑POMC-NEURON特异性消融的人群中进行MA基因ATG7。意义：代谢综合征是一个重大的全球健康问题，影响超过50岁以上的美国人口超过44％。代谢综合征通过对心脏和脑血管健康，运动活性，视力和认知以及肿瘤发展的许多不利影响之一，影响衰老人群的健康范围。当前的建议将描述MA在能量体内稳态调节中的新作用，从而为下丘脑MA的热调节奠定了预防或治疗衰老代谢综合征的基础，并以这种方式改善了年龄较大的寿命和健康范围。