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.

项目摘要 体温调节与能量平衡的紧密耦合使体温和体重 尽管环境温度发生了戏剧性的变化，但它们还是得到了防御。这项提案的一个核心目标是澄清 能量摄入量的适应性变化与环境温度的变化相结合，重点放在 对寒冷暴露的高吞噬反应。尽管未经测试，但人们已经接受了一种观点，即寒冷诱导的 吞噬功能亢进是在出现负能量状态(即体内脂肪储备减少)后开始的。 然而，我们最近的发现表明，食物摄取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，并可能先于负能量状态的发展。另外， 我们发现，我们最近的发现暗示了刺鼠相关肽(AgRP)神经元在适应性摄食中的作用 反应，因为AgRP神经元活性的增加先于冷诱导的吞噬，并且是必需的，但 而不是冷诱导的生热反应。在这里，我们提出了新的和相互关联的假设，即冷- 体温调节回路的诱导激活驱动能量消耗和食物的适应性变化 同时摄取，这些反应独立于能量变化而发生，并用于最小化能量变化 在肥胖的动物中，它们是解偶联的，从而导致体重减轻。的首要目标是 建议识别和功能表征连接体温调节和AgRP控制的神经回路。 神经元活动和相关的摄食反应。因此，这里提出的研究将不会带来新的曙光 只是关于能量平衡和食物摄入量是如何相互关联的，但这种耦合过程是如何 在肥胖的动物身上会受到干扰。拟议的研究寻求1)表征连接神经回路 对AgRP神经元激活和冷诱导的吞噬功能的温度调节和2)确定神经元如何 而在引入高脂肪饮食后，回路水平的功能障碍就会发生。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、光遗传学和体内纤维光度学 方法被利用，结合免疫组织化学和高级代谢表型。 总之，这项工作将促进对将体温调节与AgRP联系起来的神经回路的理解。 神经活动和摄食，并可能确定治疗肥胖症的新策略。