Hypothalamic Lipid-Sensing and Energy Balance

描述（由申请人提供）： 肥胖及其共病是全球性的公共卫生问题。中枢神经系统在能量平衡中的作用正在被深入研究。近年来，脂肪酸代谢与中枢神经系统对食物摄入和能量平衡的调节有关。长链脂肪酰辅酶A（LCFA：CoA）和丙二酰辅酶A都被认为是大脑脂质感应区营养物质可用性的信号。监测这种信号的脂质感受神经元以及将其整合到能量平衡调节中的机制尚不清楚。该建议的中心目的是确定相关的脂质信号和监测其浓度以调节能量平衡的神经元亚组。使用Cre/loxP DNA重组，脂肪酸代谢将在整个中枢神经系统和已知涉及能量平衡的特定下丘脑核中受到遗传干扰。肉毒碱棕榈酰转移酶-1和胞质丙二酰辅酶A脱羧酶将过表达，以分别降低下丘脑LCFA：CoA和丙二酰CoA。如果这些分子是营养可用性的信号，那么降低它们在中枢神经系统中的浓度将模拟营养缺乏，并刺激食物摄入量增加和能量消耗减少。这种方法将识别感知脂质的神经元组和被监测的脂质信号的性质。它将在体重调节的线路图中定位这种脂质传感途径，并可能为肥胖及其合并症的治疗提供新的治疗靶点。 该提案还旨在促进申请人的培训和发展，使其成为能量平衡紊乱，肥胖和糖尿病领域的熟练，独立的调查员。

DESCRIPTION (provided by applicant): Obesity and its co-morbidities are global public health problems. The role of the central nervous system in energy balance is being intensively investigated. Recently fatty acid metabolism has been implicated in the central nervous system regulation of food intake and energy balance. Long chain fatty acyl CoAs (LCFA:CoAs) and malonyl CoA have both been proposed to act as signals of nutrient availability in lipid-sensing areas of the brain. The lipid-sensing neurons that monitor this signal and the mechanism by which it is integrated it into the regulation of energy balance are unknown. The central aim of this proposal is to identify the relevant lipid signal and neuronal subgroups that monitor its concentration to modulate energy balance. Using a Cre/loxP DNA recombination, fatty acid metabolism will be genetically perturbed throughout the central nervous system and in specific hypothalamic nuclei known to be involved energy balance. Carnitine palmitoyl transferase-1 and a cytosolic malonyl CoA decarboxylase will be over expressed to decrease hypothalamic LCFA:CoAs and malonyl CoA respectively. If these molecules are signals of nutrient availability, reducing their concentration in the central nervous system will mimic nutrient deficiency and stimulate increased food intake and decreased energy expenditure. This approach will identify the neuronal groups that sense lipids and the nature of the lipid signal being monitored. It will position this lipid-sensing pathway in the wiring diagram of body weight regulation and potentially provide new therapeutic targets for the treatment of obesity and its comorbidities. This proposal is also designed to facilitate the training and development of the applicant to become a skilled, independent investigator in the areas of disordered energy balance, obesity and diabetes.