Integration of Lepr circuits for thermoregulation and energy status

尽管有大量的肥胖研究和越来越多的关于中枢和外周机制的知识， 调节食物摄入和能量消耗，治疗肥胖的生活方式干预一直是 长期不成功。 对禁食和食物限制的强大生理适应反对减肥，并被认为是 成为阻止长期维持减肥的罪魁祸首。然而，我们对这些生理现象的理解 适应和神经回路的参与是不够的。 我们对下丘脑瘦素反应神经元（POALepr和DMHLepr神经元）的研究， 表明，温度传感和能量传感集成在相同的神经回路，调节 能量消耗（EE）和食物摄入（FI）。此外，我们的数据表明，EE和FI是受管制的， 独立的电路 与此相一致，我们展示了令人信服的证据，表明温度和能量状态极大地影响着每一个 另一些是由于这些回路中神经元活动的明显变化。我们的工作假设整合了 已知的具有温度感测电路的能量感测电路，并且突出了瘦素中的重要变化 灵敏度不仅受能量感应影响，还受环境温度影响，突出了瘦素 抵抗是一种生理状态，而不是病理状态。这一新的观点是一个重要的进展， 我们对生理适应的理解，对人类和动物的研究， 健康和疾病的代谢。 本实验主要研究温度依赖性和能量依赖性的神经元回路整合 EE和FI的状态依赖性变化。 在目的1中，我们将研究投射到DMH的温敏POALepr神经元及其在DMH中的作用。 通过冷感DMHLepr抑制EE。此外，我们将表明，冷敏感DMHLepr也受到调节， 通过能量感应ARC神经元。 在目标2中，我们将研究投射到ARC的温敏POALepr神经元及其在 通过ARCPOMC神经元抑制FI。 在目的3中，我们将研究瘦素的作用和瘦素敏感性的动态变化，以选择性地 EE通过DMH投射的Lepr神经元调节，而FI通过PVN投射的Lepr神经元调节。

Despite intense obesity research and growing knowledge of central and peripheral mechanisms that modulate food intake and energy expenditure, lifestyle interventions to treat obesity have been consistently unsuccessful in the long-term. Powerful physiological adaptations to fasting and food restriction oppose weight loss and are thought to be the culprit that prevents long-term maintenance of weight loss. Yet, our understanding of these physiological adaptations and the neuronal circuits involved is insufficient. Our work on leptin responsive neurons in the hypothalamus (POALepr and DMHLepr neurons) has indicated that temperature sensing and energy sensing integrate in the same neuronal circuits that modulate energy expenditure (EE) and food intake (FI). Furthermore, our data indicate that EE and FI are regulated independent circuits. In line with this, we show compelling evidence that temperature and energy state greatly impact each other due to explicit changes in neuronal activity within these circuits. Our working hypothesis integrates known energy sensing circuits with temperature sensing circuits and highlights important changes in leptin sensitivity that are not only impacted by energy sensing but also with ambient temperature, highlighting leptin resistance as a physiological, rather than pathological condition. This novel view is an important progress for our understanding of physiological adaptations that will be important for human and animal studies of metabolism in health and disease. The proposed experiments focus on the neuronal circuit integration of temperature-dependent and energy state dependent changes in EE and FI. In Aim 1 we will investigate warm-sensing POALepr neurons that project to the DMH and their role to suppress EE via cold-sensing DMHLepr. Furthermore, we will show that cold-sensing DMHLepr are also regulated by energy sensing ARC neurons. In Aim 2 we will investigate warm-sensing POALepr neurons that project to the ARC and their role to suppress FI via anorexigenic ARCPOMC neurons. In Aim 3 we will investigate the role of leptin and dynamic changes in leptin sensitivity to selectively regulate EE via DMH-projecting Lepr neurons, while FI is regulated via PVN projecting Lepr neurons.