The dorsomedial hypothalamus integrates temperature and energy sensing signals to regulate energy expenditure.

下丘脑背内侧整合温度和能量传感信号来调节能量消耗。

• 批准号: 10619445
• 负责人: Sean Swetledge
• 金额: $ 7.65万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10619445
• 关键词: Affect; American; Axon; Body Weight; Brain; Brown Fat; Bypass; Couples; Development; Eating; Energy Metabolism; Equilibrium; Fasting; Fiber; Food Energy; GTP-Binding Protein alpha Subunits, Gs; Glutamates; Goals; Homeostasis; Hypothalamic structure; Impairment; Knock-out; Maps; Mediating; Metabolic; Modeling; Motor Neurons; Neurons; Obesity; Obesity Epidemic; Output; Pathway interactions; Peptides; Pharmacologic Substance; Photometry; Physiologic Thermoregulation; Physiological; Play; Population; Preoptic Areas; Prevention strategy; Pro-Opiomelanocortin; Regulation; Research; Rodent; Role; Signal Transduction; Site; Stimulus; Structure of nucleus infundibularis hypothalami; Temperature; Temperature Sense; Testing; Thermogenesis; Weight; Weight Gain; Work; Yin; feeding; genetic manipulation; improved; integration site; leptin receptor; neural; neuronal circuitry; novel strategies; obesity treatment; optogenetics; paraventricular nucleus; response; treatment strategy; warm temperature

ABSTRACT The two primary factors that drive changes in body weight (BW) - food intake (FI) and energy expenditure (EE) - are both regulated within the hypothalamus of the brain and respond to changes in energy availability (energy-sensing) and ambient temperature (temperature-sensing). A more comprehensive understanding of how the hypothalamus regulates food intake and energy expenditure can enhance our approach to treating obesity through a pharmaceutical and/or environmental approach that targets the relevant neurons and/or environmental strategies that promote high EE and lower FI. Research outlined in this proposal seeks to describe how temperature and energy-sensing circuits integrate with each other. Proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARC) are known to regulate FI via MC4R signaling in the paraventricular nucleus (PVN), but the PVN does not account for EE regulation in response to feeding signals (2). An article investigating Gsα deficiency in the DMH revealed that DMH-specific MC4R knockout impairs EE and resulted in BW increases without impacting FI, implying that energy-sensing signals from the ARC affect EE adaptations via the DMH (3). Our hypothesis is that the DMH is an integration site of thermoregulatory and energy-sensing signals that impact EE. Activation of warm-sensitive neurons of the preoptic area suppresses EE in response to warm temperatures, and this is traditionally thought to occur via the inhibition of cold-sensitive neurons in the DMH that promote brown adipose tissue (BAT) thermogenesis despite the recent discovery that warm sensitive POA neurons are glutamatergic (6). Additionally, the POA projects directly to sympathetic pre-motor neurons in the raphe pallidus (RPa), and it is unclear what distinctive roles the POA-DMH and POA-RPa connection play in EE regulation (5). We hypothesize that the POA-DMH connection is a critical integrator for temperature and energy state EE adaptations, while the POA-RPa might mediate only temperature-dependent EE adaptations and could bypass feeding-induced MC4R signaling in the DMH. Using optogenetics and a novel strategy known as synthetic-and-physiological- activation-assisted-circuit-mapping (SPAACM), we will investigate how the POA, DMH, RPa, and ARC interact with each other and control EE in response to changes in ambient temperature and feeding states. SPECIFIC AIM I investigates the role of energy-sensing signals in the DMH and whether there is a temperature- dependent effect on EE within this circuit. SPECIFIC AIM II focuses on the POA>DMH and POA>RPa connections and their respective contributions to thermoregulatory modulation of EE.

摘要 推动体重(BW)变化的两个主要因素-食物摄入量(FI)和能量消耗(EE) -两者都在大脑的下丘脑中进行调节，并对能量供应的变化做出反应 (能量感应)和环境温度(温度感应)。更全面地了解 下丘脑如何调节食物摄入量和能量消耗可以加强我们的治疗方法 通过针对相关神经元和/或环境的药物和/或环境方法进行肥胖 促进高EE和低FI的环境战略。这项提案中概述的研究旨在 描述温度感测电路和能量感测电路如何相互集成。前阿片黑素皮质素(POMC) 已知弓状核(ARC)中的刺鼠相关肽(AgRP)神经元通过MC4R调节FI 室旁核(PVN)中的信号传递，但PVN不解释EE对 馈电信号(2)。一篇研究DMH中Gsα缺陷的文章揭示了DMH特异性的MC4R 基因敲除会损害EE并导致体重增加，而不会影响FI，这意味着能量感应信号 从ARC通过DMH影响EE适应(3)。我们的假设是DMH是一个整合部位 影响EE的温度调节和能量传感信号。温敏性神经元的激活 视前区对温暖的温度反应会抑制EE，传统上认为这种情况会发生 通过抑制DMH中促进棕色脂肪组织(BAT)产热的冷敏感神经元 尽管最近发现热敏感的POA神经元是谷氨酸能的(6)。此外，POA 直接投射到中缝苍白带(RPA)的交感运动前神经元，目前还不清楚有什么不同 POA-DMH和POA-RPA连接在EE调节中的作用(5)。我们假设POA-DMH 连接是温度和能量状态EE适应的关键积分器，而POA-RPA 可能只调节依赖温度的EE适应，并可以绕过摄食诱导的MC4R DMH中的信号。利用光遗传学和一种被称为合成和生理的新策略- 激活辅助电路映射(SPAACM)，我们将研究POA、DMH、RPA和ARC如何相互作用 并控制EE以响应环境温度和供料状态的变化。特定的 目的研究能量敏感信号在DMH中的作用，以及DMH中是否存在温度信号。 在此电路内对EE的依赖效应。特定目标II侧重于POA&>DMH和POA&>RPA 连接以及它们各自对EE的温度调节的贡献。