Kansas Center for Metabolism and Obesity REsearch (KC-MORE) - Project 2

项目2（莫里斯）：项目摘要 肥胖是代谢性疾病发生和进展的最强独立预测因子，例如 2糖尿病与心血管疾病。体重增加是由于食物/能量摄入量增加所致 并减少总能量消耗以创造正能量平衡。能量平衡不是恒定的， 一致的，因此长期的体重增加发生作为一个总和的许多，小的积极波动， 时间范围从天到季节。这些积极的能量平衡的急性发作发生作为一个复杂的 当前致胖环境和能量稳态的不适当调节的相互作用。能源 体内平衡是通过外周神经、激素和营养信号的整合来调节的， 复杂的，相互连接的中央网络，包括下丘脑腹内侧核（VMH）。的 VMH参与调节能量平衡的两个组成部分，即能量消耗 和能量摄入，使其成为体重调节的重要组成部分。建议的主要目标 3-一年的研究计划是建立一个独立的研究线，调查线粒体的作用， 下丘脑腹内侧核神经元脂质代谢对能量稳态的调节。 已经提出激活参与VMH中的感知降低的细胞能量状态的途径， 通过急性激活神经元脂质代谢增加食物摄入。此外，抑制这些相同的 已经观察到增加全身能量消耗的途径。然而，不知道是否 这两种能量平衡成分的调节依赖于线粒体脂质代谢， VMH神经元。该建议的中心假设是VMH中的神经元线粒体脂质代谢 在暴露于能量密集饮食期间通过控制1）调节全身能量稳态调节 食物摄入和2）能量消耗。在这项提议中，我们将使用VMH特异性的PGC-1α敲除（VPGC 1a-1a）， /-）小鼠模型，研究神经元线粒体脂肪酸氧化和呼吸功能对食物的作用 空腹和饱腹激素暴露期间的摄入调节。更多的研究将检查是否 神经元线粒体脂质代谢的调节影响高脂肪/高蔗糖诱导的体重增加。作为 因此，这两组研究都将利用腺相关病毒来增加线粒体脂质代谢， VMH神经元通过PGC 1a的过度表达。

PROJECT 2 (MORRIS): PROJECT SUMMARY Obesity is the strongest independent predictor for the onset and progression of metabolic diseases, such as type 2 diabetes and cardiovascular disease. Weight gain occurs due combination of increased food/energy intake and decreased total energy expenditure to create a positive energy balance. Energy balance is not constant or consistent, and therefore long-term weight gain occurs as a sum of numerous, small positive fluctuations over time scales ranging from days to seasons. These acute episodes of positive energy balance occur as a complex interaction of the current obesogenic environment and inappropriate regulation of energy homeostasis. Energy homeostasis is regulated through the integration of peripheral neural, hormonal and nutrient signals by a complex, interconnected central network, including the ventromedial nucleus of the hypothalamus (VMH). The VMH has been observed as involved in the regulation of both components of energy balance, energy expenditure and energy intake, making it an important component of body weight regulation. The main goal of the proposed 3-year research plan is to establish an independent research line investigating the role of mitochondrial lipid metabolism in ventromedial hypothalamus neurons on the regulation of energy homeostasis. Activation of pathways involved in sensing reduced cellular energy state in the VMH have been proposed to increase food intake through acute activation of neuron lipid metabolism. Further, inhibition of these same pathways has been observed to increase whole-body energy expenditure. However, it is unknown whether regulation of these two components of energy homeostasis is dependent upon mitochondrial lipid metabolism in VMH neurons. The central hypothesis of this proposal is that neuronal mitochondrial lipid metabolism in the VMH modulates systemic energy homeostasis regulation during exposure to energy dense diets through control of 1) food intake and 2) energy expenditure. In this proposal, we will use a VMH-specific, PGC-1α knockout (VPGC1a- /-) mouse model to study the role of neuron mitochondrial fatty acid oxidation and respiratory function on food intake regulation during fasting and satiety hormone exposure. Additional studies will examine whether modulation of neuronal mitochondria lipid metabolism impacts high-fat/high-sucrose-induced weight gain. As a corollary, both sets of studies will utilize adeno-associated virus to increase mitochondrial lipid metabolism in VMH neurons through overexpression of PGC1a.