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: 10359828
• 负责人: Lisa R Beutler
• 金额: $ 38.3万
• 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/10359828
• 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; antagonist; 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 肥胖是一个惊人的公共卫生威胁与失调的长效稳态 调节新陈代谢和饱腹感的反馈，以及来自肠道的驱动进餐终止的快速作用信号。 过度食用富含糖的高度加工食品越来越多地与发展有关， 肥胖及其合并症。我们知识上的一个主要空白是理解富含碳水化合物的饮食是如何 在正常体重和肥胖动物中通过快速肠-脑通讯调节饱足感。使用模型I 率先解剖胃肠道营养输送对下丘脑的体内动力学的影响， 喂养回路，我以前曾表明，胃输注大量营养素迅速抑制人口的饥饿- 促进下丘脑中的神经元AgRP神经元。这种抑制作用与总的 注入的卡路里数量和独立的常量营养素身份，虽然分子机制是 特定的大量营养素。最近的数据表明，高脂饮食（HFD）引起的肥胖导致选择性肥胖。 减少脂肪介导的AgRP神经元抑制，支持营养过剩诱导营养特异性 沿着肠脑轴变化。然而，AgRP神经元抑制的分子机制， 碳水化合物的摄入仍然是未知的。 这里提出的工作将测试几个假设，开始解决这个问题。Aim 1使用组合 药理学和条件遗传工具，以确定快速摄食后激素释放的作用， 一群专门的胃肠道衬里细胞，称为肠内分泌细胞（EECs）， 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作用于哪些组织和细胞类型 来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-脑动力学的独特变化， 与HFD相比，由于EECs转录景观中的营养特异性变化，EECs的表达与HFD的表达不同。 这些研究将填补我们对碳水化合物摄入如何快速调节摄食的理解中的几个空白 电路活动它将阐明关键的葡萄糖释放肠道激素在介导这些动力学中的作用， 证明了关键的激素信号是必需的，并揭示了碳水化合物的过度消耗 在神经活动和EEC功能水平上改变肠-脑轴。总的来说， 这些数据将极大地促进我们对营养过剩如何导致营养素特异性变化的理解 关键的自我平衡过程。这将最终产生新的见解，治疗和预防 肥胖