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

摘要 肥胖会导致2型糖尿病和其他不利的健康后果，给我们的 医疗机构--以及肥胖患者。大脑包含调节摄食和 从长远来看，体重。其中许多系统位于控制食物摄入量的下丘脑。 和能量平衡对一系列信号的反应，包括瘦素(身体能量的荷尔蒙信号) 脑干孤束核(NTS)内储存)和摄食激活神经元。设计新的治疗方法 为了对抗肥胖，我们必须了解控制摄食和体重的大脑系统，包括 整合瘦素和后脑输入的下丘脑回路。 先前的工作表明，GABA能Lepr神经元位于下丘脑背内侧(DMH)。 在控制摄食行为，包括抑制食欲方面做出重要贡献 弓状核(ARC)AgRP神经元通过瘦素和摄食。此外，我们最近的结果显示，有几个 抑制摄食的谷氨酸能NTS神经元投射到DMH并抑制AgRP 神经元。虽然这些发现表明一组GABA能DMH LepRb神经元整合了信号 从瘦素和NTS到通过抑制AgRP神经元来抑制食物摄取，DMH包含了许多种群 具有不同功能的神经元，包括多组GABA能LepRb神经元。我们的实验室用 用于识别已知和新的LepRb神经元群体的单核RNA测序，包括一个新的 GLP-1受体标记的GABA能DMH LepRb神经元群 表达(LepRbGlp1r神经元)。我们发现LepRbGlp1r神经元在控制食物方面起着重要作用 瘦素的摄入。我们假设这些LepRbGlp1r神经元代表了GABA能的关键种群 DMH LepRb神经元整合瘦素和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 谷氨酸能NTS神经元的兴奋性传入；(2)LepRbGlp1r神经元抑制AgRP神经元并抑制 食物摄入；以及(3)沉默LepRbGlp1r神经元将增加AgRP神经元的活动，促进摄食 体重也增加了。

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.