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

喂养回路动态的快速激素调节及其对肥胖的破坏

• 批准号: 10182404
• 负责人: Lisa R Beutler
• 金额: $ 37.41万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10182404
• 关键词: Ablation; Address; Animals; Area; Automobile Driving; Behavioral; Brain; Brain Stem; Calories; Carbohydrates; Cell physiology; Cells; Cellular biology; Communication impairment; Consumption; Data; Development; Diet; Dietary Fats; Diphtheria Toxin; Eating; Enterocytes; Enteroendocrine Cell; Fatty acid glycerol esters; Feedback; Fiber; Food; Gastrointestinal tract structure; Genetic; Genetic Techniques; Genetic Transcription; Glucose; Goals; High Fat Diet; Hormonal; Hormones; Hunger; Hypothalamic structure; Infusion procedures; Ingestion; Intake; Knock-out; Knockout Mice; Knowledge; Macronutrients Nutrition; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Monitor; Mus; Neuraxis; Neurons; Neurosciences; Nucleus solitarius; Nutrient; Nutritional; Obese Mice; Obesity; Overnutrition; Pathway interactions; Pharmacology; Photometry; Population; Prevalence; Process; Public Health; Receptor Signaling; Role; Satiation; Signal Transduction; Stimulus; Stomach; Structure of beta Cell of islet; Structure of nucleus infundibularis hypothalami; Sucrose; Testing; Tissues; Vagus nerve structure; Weight; Work; absorption; base; cell type; comorbidity; conditional knockout; data integration; epigenomics; experimental study; feeding; gastric inhibitory polypeptide receptor; gastrointestinal; genetic approach; glucose metabolism; glucose uptake; gut-brain axis; hormonal signals; in vivo; increased appetite; incretin hormone; insight; novel; obesity development; obesity prevention; obesogenic; preference; receptor; relating to nervous system; response; sugar; symporter; tool

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.

项目概要 肥胖是一个令人震惊的公共健康威胁，与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作用信号驱动膳食终止。 过度食用富含糖分的高度加工食品越来越与健康的发展有关。 肥胖及其合并症。我们知识的一个主要差距是了解富含碳水化合物的饮食如何 通过快速肠脑通讯调节正常体重和肥胖动物的饱腹感。使用模型 I 率先剖析胃肠道营养输送对下丘脑体内动态的影响 喂养回路，我之前表明，大量营养素的胃输注可以迅速抑制人群的饥饿- 促进下丘脑中称为 AgRP 神经元的神经元。这种抑制与总抑制成正比 尽管分子机制是 宏量营养素特定。最近的数据表明，高脂饮食（HFD）引起的肥胖会导致选择性的肥胖。 脂肪介导的 AgRP 神经元抑制减少，支持营养过度会导致营养特异性的观点 沿着肠脑轴发生变化。然而，AgRP 神经元抑制的分子机制 碳水化合物的摄入仍然很大程度上未知。 这里提出的工作将测试几个假设来开始解决这个问题。目标 1 使用组合 药理学和条件遗传工具来定义快速摄入后激素释放的作用 胃肠道衬里细胞的特殊群体，称为肠内分泌细胞（EEC），用于驾驶 碳水化合物介导的 AgRP 神经元抑制。除了定义所需的特定分泌信号外 葡萄糖诱导的肠脑通讯，我们将确定这些激素在哪些组织和细胞类型中起作用 引起神经活动的变化。在目标 2 中，根据我们对喂食 HFD 的小鼠的结果，我们将检验假设 高碳水化合物饮食引起的肥胖会导致肠脑动力学的独特变化 与 HFD 相比，由于 EEC 转录景观中的营养特异性变化，通讯发生了变化。 这些研究将弥补我们对碳水化合物摄入如何快速调节喂养的理解上的一些差距 电路活动。它将阐明关键的葡萄糖释放肠道激素在调节这些动态中的作用， 展示哪里需要关键的激素信号传导，并揭示碳水化合物如何过度消耗 在神经活动和 EEC 功能水平上改变肠脑轴。总的来说，整合 这些数据将极大地促进我们对营养过剩如何导致特定营养变化的理解 在关键的稳态过程中。这最终将为治疗和预防带来新的见解 肥胖。