控制白色脂肪组织棕色化的神经机制研究

Obesity is one the major threats of human health. More than 100 million people in China are suffering from obesity and related disorders and this number keeps increasing each year. Obesity is due to excess accumulation of white fat tissues to a harmful extent and unfortunately, there are few safe and efficient managements to reduce fat weights. Recent studies show that the white fat tissues can be turned into brown fat like tissues (called ‘browning’) after induction by cold or other stimuli, which is very helpful to burn the excess energy and protect blood sugar and lipid from rising too high. This browning of white fat tissues also offers a new strategy for anti-obesity drug development. Unfortunately, it is still not clear for the central mechanisms that mediate the cold-induced browning of fat tissues. In the proposal, we proposed that 1) neurons in the thermoregulation center, the preoptic area, inhibit cold-induced browning, but promote heat-induced whitening of fat tissues. 2) While neurons in another thermoregulation center, the dorsomedial hypothalamus promote cold-induced browning and inhibit heat-induced whitening. 3) Brain-derived neurotrophic factor (BDNF) promotes whitening in the preoptic area, while promotes browning in the dorsomedial hypothalamus. We will test our hypothesis by combining neural activity control, and functional and biochemical tests of fat tissues. Also, we will use site-specific knockouts and neural transcriptome analysis to find new factors for anti-obesity drug development.

肥胖已成为威胁人类健康的主要因素之一。我国人口肥胖率正快速增长，已有超过1亿人口受肥胖的困扰。肥胖是由白色脂肪过度积累到有害程度的一种慢性疾病，目前鲜有高效安全的抗肥胖手段。研究表明，白色脂肪可以在低温等刺激之下，转变成为可以产热的棕色样脂肪。这种棕色化的转变有利于消耗能量和抵抗高血脂与高血糖，为抗肥胖提供了一个新的契机。令人遗憾的是，人们对低温诱导棕色化中所涉及的中枢神经机制还知之甚少。本研究中，我们根据之前的研究成果和初步实验数据，提出：1）体温调节的中枢视前区POA神经元抑制冷诱导的棕色化，而促进热诱导的白色化。2）背内侧核DMH则相反，促进冷诱导的棕色化，抑制热诱导的白色化。3）脑源性神经营养因子BDNF在POA促进脂肪白色化，而在DMH促进脂肪棕色化。我们将结合神经活性操作与脂肪生理和生化检测手段验证上述假设，并通过基因敲除和转录组学分析筛选新的因子，为抗肥胖药物提供新的靶标。

肥胖已成为威胁人类健康的主要因素之一。我国人口肥胖率正快速增长，已有超过1亿人.口受肥胖的困扰。肥胖是由白色脂肪过度积累到有害程度的一种慢性疾病，目前鲜有高效安全的抗肥胖手段。白色脂肪可以在低温等刺激之下，转变成为可以产热的棕色样脂肪。这种棕色化的转变有利于消耗能量和抵抗高血脂与高血糖，为抗肥胖提供了一个新的途径。本项目第一部分以寻找控制冷刺激诱导的白色脂肪棕色化的关键神经元及分子为研究重点，发现：1）下丘脑背内侧核的BDNF神经元参与调控脂肪产热，激活该群神经元能有效促进脂质代谢，而抑制该群神经元则会导致体重增长、糖脂代谢紊乱。2）视前区控制能耗与体温的精准信号依赖于脑干的不同输入,其中LPB pdyn神经元控制脂肪产热，激活该群神经元可高效抵抗高脂饮食导致的肥胖。以上研究成果在未来可能成为抗肥胖药物开发的重要靶点。.本项目的第二部分对小鼠的暴食和享乐性进食的奖赏机制等能量摄入的神经基础进行研究，发现：1）DH44神经元是摄入后主要氨基酸感受神经元。2）ZI神经元整合多感觉信号促进暴食与进食动机。3）ZI-PAG编码捕食行为具有时间序列，为本能刻板行为增加了灵活性。这些研究成果建立能量代谢研究范式，可为后续研究提供方法学基础。