Hypothalamic autophagy and metabolic regulation in aging

描述（由申请人提供）：代谢综合征以内脏型肥胖、高血压、高脂血症和胰岛素抵抗为特征。整个身体的能量平衡是通过营养和激素信息的整合来维持的，这些信息是由下丘脑中基底部的两个不同的神经元群，即刺肽相关肽（AgRP）和促黑素皮质素（POMC）神经元提供的。下丘脑POMC神经元表达POMC， POMC被加工成促进能量消耗的-黑素细胞刺激激素（-MSH）。巨噬（Macroautophagy， 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，由于下丘脑POMC神经元中缺乏MA的啮齿动物表现出-MSH减少、肥胖增加和葡萄糖耐受不良，因此POMC加工和-MSH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活性下降，我们现在已经证明下丘脑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，以及衰老过程中下丘脑MA减少的机制尚不清楚。本提案的总体目标是阐明失败的贡献

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.