Metabolic Pathways Involved in the CNS Regulation of Energy Balance

描述（由申请人提供）：近三分之二的美国成年人肥胖或超重（1），导致每年超过930亿美元的医疗支出（2）。尽管肥胖问题日益严重，但能量平衡的生理调节非常准确，导致热量摄入与热量支出相匹配（3）。这种精确性取决于身体对内部线索的反应能力，这些线索传递了有关长期和短期能量可用性的信息。大脑调节能量平衡，以响应营养和激素的提示，神经元脂肪酸代谢似乎是至关重要的这一机制。丙二酰辅酶A是脂肪酸合成的基本单元，当乙酰辅酶A积累时，丙二酰辅酶A是丰富的。多种厌食反应需要丙二酰辅酶A，这表明该分子在下丘脑中作为燃料传感和激素信号传导之间的联系的作用。然而，丙二酰辅酶A在关键下丘脑神经元中的关键下游作用尚未确定.在该资助申请中概述的实验旨在测试中心假设，即丙二酰辅酶A通过刺激关键下丘脑核中的哺乳动物雷帕霉素靶标（mTOR）来减少食物摄入。最近，下丘脑mTOR激活已被提出作为关键的下丘脑燃料传感器（10）。丙二酰辅酶A和mTOR都是C75（5）、瘦素（10）和CNTF（11）的显著厌食作用所必需的。这些底物如何共同作用以改变摄食行为是未知的，并且代表了本提案的关键总体目标。具体目的1：证明厌食剂刺激mTOR通路需要下丘脑丙二酰辅酶A升高。具体目的2：检验下丘脑丙二酰辅酶A升高足以诱导厌食和mTOR通路激活的假设。这些假设的测试将包括乙酰辅酶A羧化酶（ACC）的慢性药理学抑制期间的行为和分子测定，这是丙二酰辅酶A生产所必需的。我们将观察下丘脑丙二酰辅酶A富集的影响，通过敲低其降解酶，丙二酰辅酶A脱羧酶（MCD）使用腺相关病毒携带靶向基因的短发夹RNA序列的弓状沟内输注。公共卫生相关性：预计拟议的研究将阐明丙二酰辅酶A在调节食物摄入中的作用，并确定将下丘脑丙二酰辅酶A升高与食物摄入减少联系起来的下游靶点。这一贡献是显著的，因为对中枢燃料感测的理解将确定用于治疗和/或预防肥胖的新的治疗策略。

DESCRIPTION (provided by applicant): Nearly two-thirds of all American adults are obese or overweight (1), resulting in over $93 billion in medical expenditures each year (2). Despite the growing obesity problem, the physiological regulation of energy balance is remarkably accurate resulting in the matching of caloric intake to caloric expenditure (3). This precision is dependent upon the body's ability to respond to internal cues relaying information about both long-term and short-term energy availability. The brain regulates energy balance in response to nutrient and hormonal cues, and neuronal fatty acid metabolism appears to be crucial to this mechanism. Malonyl-CoA is the building block for fatty acid synthesis and is abundant when acetyl-CoA accumulates. Multiple anorectic responses require malonyl-CoA, suggesting a role for the molecule as a nexus between fuel sensing and hormonal signaling in the hypothalamus. However, the key downstream actions of malonyl- CoA in key hypothalamic neurons have yet to be defined. The experiments outlined in this grant application are aimed to test the central hypothesis that malonyl-CoA acts to decrease food intake by stimulating the mammalian Target of Rapamycin (mTOR) in key hypothalamic nuclei. Recently, hypothalamic mTOR activation has been proposed as a critical hypothalamic fuel sensor (10). Both malonyl-CoA and mTOR are required for the dramatic anorectic effects of C75 (5), leptin (10), and CNTF (11). How these substrates might act together to alter ingestive behavior is unknown and represents a key overarching goal of the present proposal. Specific Aim 1: To demonstrate that elevated hypothalamic malonyl-CoA is required for stimulation of the mTOR pathway by anorectic agents. Specfic Aim 2: To test the hypothesis that elevated hypothalamic malonyl-CoA is sufficient to induce anorexia and activation of the mTOR pathway. Tests of these hypotheses will include behavioral and molecular assays during chronic pharmacologic inhibition of acetyl-CoA carboxylase (ACC), which is required for the production of malonyl-CoA. We will observe the effects of hypothalamic malonyl-CoA enrichment, achieved via knockdown of its degrading enzyme, malonyl-CoA decarboxylase (MCD) using intraarcuate infusion of an adeno-associated virus carrying a short hairpin RNA sequence targeted to the gene. PUBLIC HEALTH RELEVANCE: The proposed studies are expected to elucidate the role of malonyl-CoA in the regulation of food intake and to identify downstream targets linking the elevation of hypothalamic malonyl-CoA to the reduction of food intake. This contribution is significant, because an understanding of central fuel sensing will identify novel therapeutic strategies for the treatment and/or prevention of obesity.