Hypothalamic autophagy and metabolic regulation in aging

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。下丘脑内侧基底区的两个不同的神经元群体--刺鼠相关肽(AgRP)和前阿片黑素皮质素(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，加工后产生黑素细胞刺激素(MSH)，促进能量消耗。巨自噬(MA)是一种通过降解溶酶体中的蛋白质和细胞器来维持细胞内环境平衡的重要机制。我们已发表的结果表明，MA在下丘脑AgRP神经元中控制食物摄入量的作用。我们发现，当下丘脑POMC神经元中缺乏MA的啮齿动物表现出-MSH减少、肥胖和糖耐量增加时，POMC的加工和-MSH的产生需要MA蛋白。在老年生物体的不同器官中已经描述了MA活性的降低，我们现在已经发现下丘脑MA随着年龄的增长也有类似的下降。MA在下丘脑-MSH产生中的作用，以及在衰老过程中减少下丘脑MA的机制尚不清楚。这项提议的总体目标是阐明失败的贡献 下丘脑MA随增龄而向代谢综合征的增龄化。为此，我们将：1)确定POMC神经元中MA的营养和激素激活是否从机械上将MSH的产生与外周能量消耗联系起来；2)表征下丘脑POMC神经元中随年龄增长和对高脂肪喂养的反应而减少MA的神经元内在机制；以及3)研究使用一种新的预定喂养干预措施恢复下丘脑MA是否逆转或阻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、下丘脑细胞系以及不同年龄对照组小鼠或那些下丘脑POMC神经元特异性去除MA基因ATG7的小鼠中进行。意义：代谢综合征是一个重大的全球健康问题，影响着超过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、运动能力、视力和认知以及肿瘤的发展等诸多不利影响之一，影响老龄人口的健康寿命。本研究将揭示MA在调节下丘脑能量动态平衡中的新作用，为MA在预防或治疗衰老代谢综合征中的治疗调控奠定基础，从而提高老年人的生活质量和健康寿命。

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.