Neurocircuits linking thermoregulation and feeding

项目摘要 体温调节与能量稳态的紧密耦合使得体温和体重能够被调节。 尽管环境温度发生了巨大变化，该提案的一个核心目标是澄清如何 能量摄入的适应性变化与环境温度的变化相结合，重点是 对冷暴露的过度吞噬反应。虽然未经检验，但人们普遍认为， 在负能量状态的发展之后引发食欲亢进（即，身体脂肪储存的损失）。 然而，我们最近的研究结果表明，食物摄入和产热增加发生迅速， 在急性冷暴露之后平行，并且可能在负能量状态的发展之前。还有， 我们发现我们最近的发现暗示了刺豚鼠相关肽（Agrp）神经元在适应性摄食中的作用。 由于Agrp神经元活性的增加先于冷诱导的摄食过多，并且是冷诱导的摄食过多所需的， 而不是冷诱导的产热反应。在这里，我们提出了新的和相互关联的假设，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 同时摄入，这些反应独立于能量变化而发生，并使能量变化最小化 平衡，并且它们在肥胖动物中解偶联，导致体重减轻。的首要目标 一个建议是识别和功能性地描述连接体温调节和Agrp控制的神经回路 神经元活动和相关的进食反应。因此，本文提出的研究将揭示新的光， 能量平衡和食物摄入是如何相互耦合的， 在肥胖的动物中变得混乱。拟议的研究寻求1）描述神经回路， 温度调节对Agrp神经元激活和冷诱导的摄食过多的影响，以及2）确定神经元如何 并且在引入高脂肪饮食后发生回路水平功能障碍。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、光遗传学和体内纤维光度学 结合免疫组织化学和先进的代谢表型分析，使用这些方法。 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。 神经元活动和进食，并可能确定治疗肥胖症的新策略。

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.