Neurocircuits linking thermoregulation and feeding

连接体温调节和进食的神经回路

• 批准号: 10347362
• 负责人: Jennifer Dezet Deem
• 金额: $ 10.79万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347362
• 关键词: Acute; Animals; Behavioral; Body Temperature; Body Temperature Changes; Body Weight; Body Weight decreased; Body fat; Brain; Coupled; Coupling; Cutaneous; Data; Defect; Development; Eating; Energy Intake; Energy Metabolism; Environment; Exposure to; Fatty acid glycerol esters; Fiber; Functional disorder; Future; Goals; High Fat Diet; Homeostasis; Hyperphagia; Hypothalamic structure; Impairment; Internal Ribosome Entry Site; Light; Link; Literature; Mammals; Maps; Medial Dorsal Nucleus; Modeling; Modernization; Mus; Neurons; Neurosciences; Normal Range; Obesity; Peptides; Photometry; Physiologic Thermoregulation; Physiological; Play; Population; Preoptic Areas; Process; Reporting; Role; Secondary to; Societies; Structure of nucleus infundibularis hypothalami; System; Techniques; Temperature; Thermogenesis; Time; Tyrosine 3-Monooxygenase; Work; base; cost; diet-induced obesity; energy balance; excessive weight gain; falls; feeding; in vivo; metabolic phenotype; neural circuit; neuronal circuitry; novel; novel strategies; obesity treatment; optogenetics; paraventricular nucleus; pituitary adenylate cyclase activating polypeptide; preservation; response

Project Summary The tight coupling of thermoregulation to energy homeostasis allows body temperature and body weight to be defended, despite dramatic changes in ambient temperature. A central goal of this proposal is to clarify how adaptive changes in energy intake are coupled to changes in ambient temperature, with a focus on the hyperphagic response to cold exposure. Although untested, it has been an accepted view that cold-induced hyperphagia is initiated following the development of a negative energy state (i.e., a loss of body fat stores). However, our recent findings demonstrate that food intake and increases in heat production occur rapidly and in parallel following acute cold exposure, and likely precede the development of a negative energy state. Also, we find our recent findings implicate a role for agouti-related peptide (Agrp) neurons in the adaptive feeding response since increases of Agrp neuron activity precede and are required for cold-induced hyperphagia, but not cold-induced thermogenic responses. Here, we propose the novel and interrelated hypotheses that cold- induced activation of thermoregulatory circuits drive adaptive changes of both energy expenditure and food intake concurrently, that these responses occur independently of and serve to minimize changes in energy balance, and that they are uncoupled in obese animals, leading to weight loss. The overarching goal of the proposal is to identify and functionally characterize the neurocircuitry linking thermoregulation to control of Agrp neuronal activity and associated feeding responses. Studies proposed herein will, therefore, shed new light not only on how energy homeostasis and food intake are coupled to one another, but how this coupling process becomes disrupted in obese animals. Proposed studies seek 1) to characterize neurocircuits that link thermoregulation to Agrp neuron activation and cold-induced hyperphagia and 2) to determine how neuronal and circuit-level dysfunction occurs following the introduction of a high-fat diet. To accomplish this, we will use state-of-the-art neuroscience techniques including chemogenetics, optogenetics, and in vivo fiber photometry approaches are utilized, in combination with immunohistochemical and advanced metabolic phenotyping. Together, this work will advance the understanding of the neurocircuitry linking thermoregulation to Agrp neuronal activity and feeding and may identify novel strategies for the treatment of obesity.

项目概要 体温调节与能量稳态的紧密结合使体温和体重能够 尽管环境温度发生了巨大变化，但仍然受到保护。该提案的中心目标是阐明如何 能量摄入的适应性变化与环境温度的变化相结合，重点是 对寒冷暴露的贪食反应。尽管未经测试，但人们普遍认为，寒冷会导致 食欲亢进是在负能量状态（即体内脂肪储存减少）发展后开始的。 然而，我们最近的研究结果表明，食物摄入和热量产生的增加发生得很快，而且 在急性寒冷暴露后同时发生，并且可能在负能量状态的发展之前发生。还， 我们发现我们最近的发现暗示了刺豚鼠相关肽（Agrp）神经元在适应性进食中的作用 因为 Agrp 神经元活性的增加先于寒冷引起的食欲亢进，并且是寒冷引起的食欲亢进所必需的反应，但是 不是寒冷引起的生热反应。在这里，我们提出了新颖且相互关联的假设，即冷- 温度调节回路的诱导激活驱动能量消耗和食物的适应性变化 同时摄入，这些反应独立发生并有助于最大限度地减少能量变化 平衡，并且它们在肥胖动物中是解耦的，从而导致体重减轻。该组织的总体目标是 提议是识别和功能表征连接温度调节和 Agrp 控制的神经回路 神经元活动和相关的进食反应。因此，本文提出的研究将提供新的启示，而不是 仅关于能量稳态和食物摄入如何相互耦合，但这种耦合过程如何 在肥胖动物中会被破坏。拟议的研究寻求 1) 表征连接的神经回路 温度调节对 Agrp 神经元激活和寒冷诱导的食欲亢进的影响，以及 2) 确定神经元如何调节 引入高脂肪饮食后会出现回路水平功能障碍。为了实现这一点，我们将使用 最先进的神经科学技术，包括化学遗传学、光遗传学和体内光纤光度测定 这些方法与免疫组织化学和先进的代谢表型分析相结合。 总之，这项工作将促进对连接温度调节与 Agrp 的神经回路的理解 神经元活动和进食，可能会确定治疗肥胖的新策略。