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 肥胖促进2型糖尿病和其他不良健康结果，给我们带来重大负担 医疗机构以及肥胖症患者。大脑包含调节喂养和的系统 长期体重。这些系统中有许多位于控制食物摄入的下丘脑 和能量稳态，以响应许多信号，包括瘦素（人体能量的激素信号 商店）和脑干核核核（NTS）中的喂养激活的神经元。设计新疗法 为了打击肥胖，我们必须了解控制喂养和体重的大脑系统，包括 下丘脑回路，这些电路整合了瘦素和后脑的输入。 先前的工作表明，驻留于背部下丘脑（DMH）中的GABA能LEPR神经元 对控制喂养行为的控制做出重要贡献，包括抑制甲虫 通过瘦素和喂养，弧形核（ARC）AGRP神经元。此外，我们最近的结果表明了几个 食物摄入抑制谷氨酸能NTS神经元的群体向DMH抑制AGRP 神经元。尽管这些发现表明，GABA能DMH LEPRB神经元的群体整合了信号 从瘦素和NTS来抑制AGRP神经元抑制食物摄入，DMH包含许多人群 具有不同功能的神经元，包括多组GABA能LEPRB神经元。我们的实验室使用了 单核RNA测序以鉴定LEPRB神经元的已知和新型种群，包括一种新颖 以胰高血糖素样肽1（GLP-1）受体（GLP1R）标记的GABA能DMH LEPB神经元的种群 表达（LepRBGLP1R神经元）。我们发现LepRBGLP1R神经元在控制食物中起着重要作用 瘦素的摄入量。我们假设这些LEPRBGLP1R神经元代表了GABA能量的关键种群 DMH LEPRB神经元整合了瘦素和NTS信号以通过抑制AGRP来抑制食物的摄入量 神经元。为了检验这一总体假设，我们将测试以下概念：（1）DMH LEPRBGLP1R神经元直接接收 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； （3）沉默的LEPRBGLP1R神经元将增加AGRP神经元的活性并促进喂养 和体重增加。