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.

项目摘要 肥胖是与长效稳态失调相关的惊人的公共卫生威胁 调节新陈代谢和饱腹感的反馈，以及来自肠道驱动餐点的快速表演信号。 过度食用富含糖的高度加工食品越来越涉及 肥胖及其合并症。我们所知的一个主要差距是了解碳水化合物富含饮食的方式 通过正常体重和肥胖动物中的快速肠脑通信来调节满足。使用模型i 开创性剖析胃肠道营养递送对下丘脑体内动态的影响 喂养电路，我先前表明，大量营养素的胃输注迅速抑制了饥饿的种群 在称为AGRP神经元的下丘脑中促进神经元。这种抑制与总数成正比 尽管分子机制是 大量营养特异性。最近的数据表明，高脂饮食（HFD）诱导的肥胖导致选择性 减少脂肪介导的AGRP神经元抑制作用，支持过度营养诱导营养特异性的观念 沿肠道轴变化。但是，AgRP神经元抑制的分子机制 碳水化合物的摄入在很大程度上仍然未知。 这里提出的工作将检验一些假设，以开始解决这个问题。 AIM 1使用组合 药理学和有条件的遗传工具，以定义从A 驱动胃肠道细胞的专业人群被称为肠内分泌细胞（EEC） 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 葡萄糖引起的肠道通信，我们将确定这些激素的组织和细胞类型 引起神经活动的变化。在AIM 2中，根据我们在HFD喂养的小鼠中的结果，我们将检验假设 高碳水化合物饮食引起的肥胖导致肠道动力学的独特变化 与HFD相比，由于EEC的转录景观的营养特异性变化而导致的HFD相比。 这些研究将缩小我们对碳水化合物摄入量如何快速调节喂养的几个差距 电路活动。它将阐明关键葡萄糖释放的肠激素在介导这些动力学中的作用， 证明需要临界激素信号的位置，并揭示碳水化合物的过度消费 在神经活动和EEC功能的水平上更改肠道轴。共同的整合 这些数据将大大提高我们对过度营养如何导致营养特异性变化的理解 在关键的稳态过程中。这最终将产生有关治疗和预防的新颖见解 肥胖。