Rapid hormonal modulation of feeding circuit dynamics and its disruption in obesity

项目总结 肥胖是一种令人震惊的公共健康威胁，与两种长效体内平衡失调有关 调节新陈代谢和饱腹感的反馈，以及来自肠道的快速反应信号，推动饮食终止。 过量食用富含糖分的深度加工食品日益与糖尿病的发生有关。 肥胖症及其并存。我们知识中的一个主要差距是理解富含碳水化合物的饮食是如何 在正常体重和肥胖的动物中，通过快速的肠道-大脑通讯来调节饱腹感。使用模型I 首创剖析胃肠营养输送对下丘脑活体动力学的影响 我之前的研究表明，胃内摄入大量营养素可以迅速抑制饥饿感-- 促进下丘脑中的神经元，称为AgRP神经元。这种抑制与总量成正比 摄入的卡路里数量，与大量营养素的特性无关，尽管分子机制是 特定的常量营养素。最近的数据显示，高脂肪饮食(HFD)导致的肥胖会导致选择性的 脂肪介导的AgRP神经元抑制减少，支持过度营养导致营养特异性的观点 沿着肠轴-脑轴的变化。然而，银杏叶提取物诱导AgRP神经元抑制的分子机制 碳水化合物的摄取在很大程度上仍不清楚。 这里提出的工作将检验几个假设，以开始解决这个问题。AIM 1使用组合 药理学和条件性遗传工具来定义摄食后激素快速释放的作用 在驾驶中称为肠内分泌细胞(EECS)的胃肠道衬里细胞的专门群体 碳水化合物介导的AgRP神经元抑制。除了定义特定的秘密信号所需的 我们将确定这些激素在哪些组织和细胞类型中起作用 以引起神经活动的变化。在目标2中，基于我们在喂食HFD的小鼠身上的结果，我们将检验这一假设 高碳水化合物饮食诱导的肥胖会导致肠脑动力学的独特变化 与HFD相比，由于EECS转录版图中营养特定的变化，导致了与HFD的通信。 这些研究将填补我们对碳水化合物摄入量如何快速调节摄食的理解上的几个空白。 电路活动。它将阐明关键的葡萄糖释放胃肠激素在调节这些动态过程中的作用， 说明哪些方面需要关键激素信号，并揭示碳水化合物如何过度摄入 在神经活动和EEC功能的水平上改变肠-脑轴。总体而言， 这些数据将极大地促进我们对过度营养如何导致营养特异性变化的理解 在关键的动态平衡过程中。这最终将为治疗和预防糖尿病带来新的见解。 肥胖。

PROJECT SUMMARY Obesity is a staggering public health threat associated with dysregulation of both long-acting homeostatic feedback that modulates metabolism and satiety, and fast acting signals from the gut driving meal termination. Excessive consumption of highly processed foods rich in sugar is increasingly implicated in the development of obesity and its comorbidities. A major gap in our knowledge is to understand how carbohydrate-rich diets modulate satiation via rapid gut-brain communication in normal weight and obese animals. Using a model I pioneered to dissect the effects of gastrointestinal nutrient delivery on the in vivo dynamics of hypothalamic feeding circuits, I previously showed that gastric infusion of macronutrients rapidly inhibits a population of hunger- promoting neurons in the hypothalamus known as AgRP neurons. This inhibition is proportional to the total number of calories infused and independent of macronutrient identity, though the molecular mechanisms are macronutrient specific. More recent data show that obesity induced by a high-fat diet (HFD) results in a selective decrease in fat-mediated AgRP neuron inhibition, supporting the idea that over-nutrition induces nutrient-specific changes along the gut-brain axis. However, the molecular mechanisms of AgRP neuron inhibition induced by carbohydrate ingestion remain largely unknown. The work proposed here will test several hypotheses to begin addressing this question. Aim 1 uses a combination of pharmacologic and conditional genetic tools to define a role for rapid post-ingestive hormone release from a specialized population of gastrointestinal tract-lining cells known as enteroendocrine cells (EECs) in driving carbohydrate-mediated AgRP neuron inhibition. In addition to defining the specific secreted signals required for glucose-induced gut-brain communication, we will determine in which tissues and cell types these hormones act to elicit changes in neural activity. In Aim 2, based upon our results in mice fed a HFD, we will test the hypothesis that obesity induced by high-carbohydrate diets results in unique changes in the dynamics of gut-brain communication compared to HFD due to nutrient-specific changes in the transcriptional landscape of EECs. These studies will close several gaps in our understanding of how carbohydrate intake rapidly modulates feeding circuit activity. It will clarify the role of key glucose-released gut hormones in mediating these dynamics, demonstrate where critical hormone signaling is required, and reveal how carbohydrate overconsumption changes the gut-brain axis at the levels of both neural activity and EEC function. Collectively, the integration of these data will significantly advance our understanding of how over-nutrition leads to nutrient-specific changes in critical homeostatic processes. This will ultimately yield novel insights into the treatment and prevention of obesity.