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

科学抽象 虽然10%的体重减轻可以显著降低患肥胖相关糖尿病和心脏病的风险， 疾病，只有不到20%的人达到并保持这种体重减轻。因此，肥胖是 在美国的医疗保健费用中占了很大一部分。食用上述可口食物 自我平衡需要（基于奖励的喂养）可能是体重恢复的原因。腹侧被盖 腹侧被盖区（VTA）多巴胺神经元在基于奖励的进食中起关键作用。代谢状态影响 奖励电路然而，这种调节的机制尚不清楚。横向 下丘脑区域（LHA）食欲素葡萄糖抑制（GI）神经元，其提供兴奋性输入到下丘脑区域（LHA）。 腹侧被盖区多巴胺神经元可能是代谢状态和基于奖励的进食之间的重要联系。 例如，食欲素介导禁食诱导的奖励性进食增加。我们的初步 数据显示，禁食也降低了葡萄糖对LHA食欲素-GI神经元的抑制作用， 在低葡萄糖下增加激活。这个提议检验了减肥增加的假设 通过葡萄糖缺乏激活LHA食欲素-GI神经元。这种葡萄糖敏感性的变化强化了 通过引起腹侧被盖区多巴胺上谷氨酸信号的持续变化， 神经元因此，餐前葡萄糖的降低可以增加随后一餐的摄入。 三个具体目标将在体外和体内检验这一假设：1）确定体重减轻是否 增强食欲素GI神经元对降低的葡萄糖的反应; 2）确定体重减轻是否 以葡萄糖和食欲素依赖的方式增强腹侧被盖区多巴胺神经元的突触可塑性; 3） 确定LHA葡萄糖水平升高是否减弱了禁食和体重减轻对 基于奖励的行为这些研究将增加对潜在机制的理解 实现和维持减肥的困难。

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.