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: 8826003
• 负责人: Rajat Singh
• 金额: $ 19.2万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826003
• 关键词: Ablation; Address; Adipocytes; Adverse effects; Affect; Age; Age-Years; Aging; Appetite Regulation; 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; 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。全身能量平衡是通过整合营养和激素信息的两个不同的神经元群体在下丘脑中，刺豚鼠相关肽（AgRP）和阿黑皮素原（POMC）神经元。下丘脑POMC神经元表达POMC，其被加工以产生促进能量消耗的<$-黑素细胞刺激激素（<$-MSH）。大自噬（Macroautophagy，MA）是通过降解溶酶体中的蛋白质和细胞器来维持细胞内环境稳定的重要机制。我们发表的研究结果表明，MA在下丘脑AgRP神经元中控制食物摄入的作用。我们已经发现，MA蛋白是POMC加工和<$-MSH产生所必需的，因为下丘脑POMC神经元中缺乏MA的啮齿动物显示<$-MSH减少，肥胖和葡萄糖耐受不良增加。在老年生物体的不同器官中已经描述了MA活性的降低，我们现在已经证明了下丘脑MA随着年龄的增长也有类似的降低。MA在下丘脑生成<$-MSH中的作用，以及在衰老过程中降低下丘脑MA的机制尚不清楚。本提案的总体目标是阐明 下丘脑MA随着年龄的增长而向代谢综合征的老龄化发展。为此，我们将：1）确定POMC神经元中MA的营养和激素激活是否与POMC神经元中MA的机制有关。-MSH产生对外周能量消耗的影响，2）表征随年龄和响应于高脂肪喂养而降低下丘脑POMC神经元中MA的神经元-内在机制，以及3）检查是否使用新的预定的-喂养干预逆转或防止衰老代谢综合征的发展。这些研究将在原代下丘脑神经元、下丘脑细胞系和不同年龄对照小鼠或具有MA基因ATG 7的下丘脑POMC-神经元特异性消融的小鼠的队列中进行。重要性：代谢综合征是一个重要的全球性健康问题，影响超过44%的50岁以上的美国人口。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发展的许多不利影响之一来影响老龄化人群的健康寿命。目前的建议将描绘一个新的作用，MA在下丘脑调节能量稳态，设置下丘脑MA的治疗性调制的基础上，预防或治疗代谢综合征的老化，并以这种方式提高生活质量和健康寿命的老年人。