Role for Glucose-Inhibited Orexin Neurons in Weight Regain Following Dieting

《科学文摘》 尽管10%的体重减轻显著降低了肥胖相关糖尿病和心脏病的风险 在这种疾病下，只有不到20%的人实现并保持这种减肥效果。因此，肥胖是 美国医疗保健费用的很大一部分。进食上述美味食品 动态平衡需求(基于奖励的喂养)可能是体重恢复的一个因素。腹侧被盖 区(VTA)多巴胺神经元在基于奖赏的摄食中起着关键作用。代谢状态的影响 奖励电路。然而，这一规定背后的机制尚不清楚。侧向 下丘脑区(LHA)食欲素葡萄糖抑制(GI)神经元为 VTA多巴胺神经元可能是代谢状态和基于奖励的喂养之间的重要联系。 例如，食欲素调节禁食诱导的基于奖励的喂养增加。我们的预赛 数据显示，禁食还可减轻葡萄糖对LHA增食欲素-GI神经元的抑制作用 在低糖状态下的激活增加。这项提议检验了减肥增加的假设。 葡萄糖缺乏对LHA增食欲素胃肠神经元的激活作用这种葡萄糖敏感度的变化强化了 通过引起VTA多巴胺上谷氨酸信号的持续变化来实现基于奖励的喂养 神经元。因此，餐前血糖的降低可能会增加下一餐的摄入量。 三个特定的目标将在体外和体内检验这一假说：1)确定体重减轻 增强食欲素胃肠神经元对血糖降低的反应；2)确定体重是否减轻 以葡萄糖和食欲素依赖的方式增强VTA多巴胺神经元的突触可塑性；3) 确定LHA血糖水平升高是否会减弱禁食和减肥对 基于奖励的行为。这些研究将增加对潜在机制的理解。 在实现和保持减肥方面存在困难。

Scientific Abstract Although a 10% weight loss significantly reduces the risk of obesity-associated diabetes and heart disease, fewer than 20% of individuals achieve and maintain this weight loss. Thus, obesity underlies a large portion of health care costs in the United States. Consumption of palatable foods above homeostatic needs (reward-based feeding) is a likely contributor to weight regain. Ventral tegmental area (VTA) dopamine neurons play a key role in reward-based feeding. Metabolic state influences reward circuitry. However the mechanisms underlying this regulation are unclear. The lateral hypothalamic area (LHA) orexin glucose-inhibited (GI) neurons which provide excitatory input to the VTA dopamine neurons may be an important link between metabolic status and reward-based feeding. For example, orexin mediates the fasting-induced increase in reward-based feeding. Our preliminary data show that fasting also reduces the inhibitory effect of glucose on LHA orexin-GI neurons leading to increased activation in low glucose. This proposal tests the hypothesis that weight loss increases activation of LHA orexin-GI neurons by glucose deficit. This change in glucose sensitivity reinforces reward-based feeding by causing persistent changes in glutamate signaling onto the VTA dopamine neurons. As a result pre-prandial glucose decreases could enhance intake of the subsequent meal. Three Specific Aims will test this hypothesis in vitro and in vivo: 1) Determine whether weight loss enhances the response of orexin GI neurons to decreased glucose; 2) Determine whether weight loss enhances synaptic plasticity in VTA dopamine neurons in a glucose and orexin dependent manner; 3) Determine whether increased LHA glucose level attenuates the effects of fasting and weight loss on reward based behavior. These studies will increase understanding of the mechanisms underlying difficulties in achieving and maintaining weight loss.