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.

抽象的 驱动体重变化（BW）的两个主要因素 - 食物摄入量（FI）和能量消耗（EE） - 在大脑的下丘脑内都受到调节，并应对能量可用性的变化 （能量感应）和环境温度（温度感应）。对 下丘脑如何调节食物摄入和能量消耗可以增强我们的治疗方法 通过针对相关神经元和/或的药物和/或环境方法的肥胖症 促进高EE和较低FI的环境策略。该提案中概述的研究试图 描述温度和能量感应电路如何相互整合。 proopiomelanocortin（POMC） 已知弧形核us（ARC）中与Agouti相关的肽（AGRP）神经元通过MC4R调节FI 室室核中的信号传导（PVN），但PVN并未解释EE的调节。 进食信号（2）。 DMH中调查GSα缺乏症的一篇文章表明DMH特异性MC4R 敲除损害EE并导致BW增加而不会影响FI，这意味着能量感应信号 来自ARC通过DMH影响EE适应（3）。我们的假设是DMH是一个集成站点 影响EE的热调节和能量信号信号。激活热敏性神经元 原始区域会抑制EE，以响应温暖的温度，这在传统上被认为会发生 通过抑制DMH中的冷敏感神经元促进棕色脂肪组织（BAT）热生成 尽管最近发现温暖敏感的POA神经元是谷氨酸能的（6）。另外，POA 直接向Raphe Pallidus（RPA）中的同情运动前神经元进行项目，目前尚不清楚什么独特的 在EE法规中扮演POA-DMH和POA-RPA连接的角色（5）。我们假设POA-DMH 连接是温度和能量状态适应的关键积分器，而POA-RPA 可能仅介导温度依赖的EE适应，并可以绕过进食诱导的MC4R 在DMH中发出信号。使用光遗传学和一种新型策略，称为合成和生理学 - 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 彼此之间，并控制了环境温度和进食状态变化的EE。具体的 目的我研究了能量密度信号在DMH中的作用，以及是否存在温度 该电路中对EE的依赖性影响。特定的目标II专注于POA> DMH和POA> rpa 连接及其对EE热调节调制的各自贡献。