Integration of Lepr circuits for thermoregulation and energy status

尽管密集的肥胖研究和对中枢和外周机制的日益了解 调节食物摄入量和能量消耗，生活方式干预治疗肥胖一直是始终如一的 从长远来看是不成功的。 对禁食和食物限制的强大生理适应反对减肥，并被认为 成为阻止长期减肥的罪魁祸首。然而，我们对这些生理因素的理解 适应性和所涉及的神经元回路是不够的。 我们对下丘脑瘦素反应神经元(POALepr和DMHLepr神经元)的研究有 表明温度感知和能量感知整合在相同的神经元回路中， 能量消耗(EE)和食物摄入量(FI)。此外，我们的数据表明，EE和FI是受调控的 独立电路。 与此相一致，我们展示了令人信服的证据，证明温度和能量状态对彼此都有很大影响 另一些则是由于这些回路内神经元活动的明显变化。我们的工作假说整合了 已知的具有温度传感电路的能量传感电路，并突出了瘦素的重要变化 敏感度不仅受能量感应的影响，还受环境温度的影响，突出瘦素 抵抗力是一种生理状态，而不是病理状态。这一新颖的观点是对 我们对生理适应的理解将对人类和动物研究 健康和疾病中的代谢。 计划中的实验将重点放在依赖温度和能量的神经元回路的整合上。 EE和FI中的状态相关更改。 在目标1中，我们将研究投射到DMH的温敏POALepr神经元及其在 通过冷敏DMHLepr抑制EE。此外，我们将展示冷敏DMHLepr也受到调控 通过对ARC神经元进行能量感应。 在目标2中，我们将研究投射到ARC的温敏POALepr神经元及其在 通过厌食性ARCPOMC神经元抑制FI。 在目标3中，我们将研究瘦素的作用和动态变化在瘦素选择性地 EE通过DMH投射的Lepr神经元调节，而FI则通过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.