Mechanisms of action for dorsomedial hypothalamic Lepr-Glp1r neurons that control feeding and energy balance

控制摄食和能量平衡的下丘脑背内侧 Lepr-Glp1r 神经元的作用机制

• 批准号: 10748011
• 负责人: Allision Duensing
• 金额: $ 4.74万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748011
• 关键词: Ablation; Adult; Appetite Stimulants; Body Weight; Brain; Brain Stem; Cardiovascular Diseases; Cell Nucleus; Cells; Central Nervous System; Data; Desire for food; Detection; Diabetes Mellitus; Eating; Exhibits; Fasting; Feedback; Feeding behaviors; Food Energy; GLP-I receptor; Gene Expression Regulation; Glutamates; Health; Healthcare; Heart Diseases; Homeostasis; Hypothalamic structure; Incidence; Institution; Laboratories; Leptin; Modeling; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Peptides; Play; Population; Population Control; Prevalence; Pro-Opiomelanocortin; Receptor Signaling; Regulation; Role; Satiation; Signal Transduction; Site; Structure of dorsomedial hypothalamic nucleus; Structure of nucleus infundibularis hypothalami; System; Testing; Tetanus Toxin; Therapeutic Intervention; Weight Gain; Work; combat; design; diet-induced obesity; energy balance; feeding; hindbrain; hormonal signals; improved; in vivo; inhibitor; leptin receptor; molecular marker; new therapeutic target; novel; novel therapeutics; obese patients; obesity treatment; receptor expression; response; restraint; single nucleus RNA-sequencing

ABSTRACT Obesity promotes type 2 diabetes and other adverse health outcomes, placing a significant burden on our healthcare institutions- as well as patients with obesity. The brain contains systems that modulate feeding and body weight over the long term. Many of these systems reside in the hypothalamus, which controls food intake and energy homeostasis in response to a host of signals, including leptin (a hormonal signal of body energy stores) and feeding-activated neurons in the brainstem nucleus tractus solitarius (NTS). To design new therapies to combat obesity we must understand the brain systems that control feeding and body weight, including the hypothalamic circuits that integrate input from leptin and the hindbrain. Prior work demonstrated that GABAergic Lepr neurons that reside in the dorsomedial hypothalamus (DMH) make important contributions to the control of feeding behavior, including in the suppression of orexigenic arcuate nucleus (ARC) AgRP neurons by leptin and feeding. Additionally, our recent results showed that several populations of food intake-suppressing glutamatergic NTS neurons project to the DMH and inhibit AgRP neurons. While these finding suggest that a population of GABAergic DMH LepRb neurons integrates signals from leptin and the NTS to suppress food intake by inhibiting AgRP neurons, the DMH contains many populations of neurons with different functions, including multiple groups of GABAergic LepRb neurons. Our laboratory used single nucleus RNA sequencing to identify known and novel populations of LepRb neurons, including a novel population of GABAergic DMH LepRb neurons marked by glucagon-like peptide 1 (GLP-1) receptor (Glp1r) expression (LepRbGlp1r neurons). We found that LepRbGlp1r neurons play essential roles in the control of food intake by leptin. We hypothesize that these LepRbGlp1r neurons represent the crucial population of GABAergic DMH LepRb neurons that integrate signals from leptin and the NTS to suppress food intake by inhibiting AGRP neurons. To test this overall hypothesis, we will test the notions that: (1) DMH LepRbGlp1r neurons receive direct excitatory input from glutamatergic NTS neurons; (2) LepRbGlp1r neurons inhibit AgRP neurons and suppress food intake; and (3) silencing LepRbGlp1r neurons will increase the activity of AgRP neurons and promote feeding and weight gain.

抽象的 肥胖会促进 2 型糖尿病和其他不良健康结果，给我们带来沉重负担 医疗机构以及肥胖患者。大脑包含调节进食和进食的系统 长期体重。其中许多系统位于控制食物摄入的下丘脑 和能量稳态响应一系列信号，包括瘦素（身体能量的激素信号） 储存）和脑干孤束核（NTS）中进食激活的神经元。设计新疗法 为了对抗肥胖，我们必须了解控制进食和体重的大脑系统，包括 下丘脑回路整合来自瘦素和后脑的输入。 先前的工作表明，位于下丘脑背内侧 (DMH) 的 GABA 能 Lepr 神经元 对控制摄食行为做出重要贡献，包括抑制食欲素 弓状核（ARC）AgRP神经元受瘦素和喂养。此外，我们最近的结果表明，一些 抑制食物摄入的谷氨酸能 NTS 神经元群投射到 DMH 并抑制 AgRP 神经元。虽然这些发现表明 GABA 能 DMH LepRb 神经元群体整合信号 瘦素和 NTS 通过抑制 AgRP 神经元来抑制食物摄入，DMH 包含许多群体 具有不同功能的神经元，包括多组 GABA 能 LepRb 神经元。我们实验室用的 单核 RNA 测序可识别已知和新的 LepRb 神经元群体，包括一种新的 由胰高血糖素样肽 1 (GLP-1) 受体 (Glp1r) 标记的 GABA 能 DMH LepRb 神经元群 表达（LepRbGlp1r 神经元）。我们发现 LepRbGlp1r 神经元在食物控制中发挥重要作用 瘦素的摄入。我们假设这些 LepRbGlp1r 神经元代表 GABA 能的关键群体 DMH LepRb 神经元整合来自瘦素和 NTS 的信号，通过抑制 AGRP 来抑制食物摄入 神经元。为了检验这一总体假设，我们将检验以下概念：(1) DMH LepRbGlp1r 神经元直接接收 来自谷氨酸能 NTS 神经元的兴奋性输入； (2) LepRbGlp1r神经元抑制AgRP神经元并抑制 食物摄入量； (3)沉默LepRbGlp1r神经元会增加AgRP神经元的活性并促进摄食 和体重增加。