Role of the Pinealocyte-Derived Melatonin on the Autonomic Regulation of Energy Homeostasis

能量稳态（或平衡）是通过控制能量摄入和能量消耗来实现的。能量消耗包括各种成分，包括棕色脂肪细胞调节产热。棕色脂肪细胞存在于经典棕色脂肪组织（BAT）和米色脂肪组织（BeAT）中。与食物摄入的控制类似，BAT和BeAT产热的控制也受到关于能量储备的稳态信号的影响。BAT和BeAT由交感神经系统（SNS）密集地支配，并且在主要在下丘脑内发现的脑核的控制下。 除了被调节的能量平衡状态，调节产热的控制也调制的外部线索，包括光周期，其在BAT和BeAT产热和代谢活动的作用需要解开。光周期减弱了松果体细胞产生的褪黑激素的产生，褪黑激素在没有光的情况下释放。褪黑激素的产热/稳态作用的脑部位和机制在很大程度上仍有待阐明。 拟议的研究计划的总体目标是进一步研究光周期和褪黑激素通过BAT和BeAT产热和代谢活动影响能量稳态的机制。我们建议使用最先进的方法，包括化学遗传学和转基因，靶向褪黑激素系统，并解开其各种成分（松果体细胞和神经元表达褪黑激素受体MT 1和MT 2）对能量平衡和BAT和BeAT产热和代谢活动的作用。具体而言，我们提出（i）描绘增强或抑制的松果体褪黑激素的产生对能量稳态的调节和BAT和BeAT产热和代谢活动的控制的影响;（ii）决定重新─建立褪黑激素节律性调节能量稳态和控制BAT和BeAT产热和代谢活动的小鼠受到短期或长光周期;以及（iii）确定褪黑激素在调节能量稳态和控制BAT和BeAT产热和代谢活性中的作用的脑部位和机制。我们将使用化学遗传学方法来控制小鼠的褪黑激素生产，该方法被称为设计师受体专门由设计师药物激活（DREADD）。将进行身体成分测定以及间接热量测定。BAT或BeAT产热能力将通过测量产热/代谢基因（如Ucp 1、Dio 2、Pgc 1a、Prdm 16、Cpt 1）的表达来评估。我们将使用正电子发射断层扫描/计算机断层扫描（PET/CT）来评估BAT和BeAT的产热/代谢活动。PET示踪剂11 C-乙酸酯将被授权测量氧化活性。

Energy homeostasis (or balance) is achieved through controls exerted on energy intake and energy expenditure. Energy expenditure comprises various components that include brown adipocyte regulatory thermogenesis. Brown adipocytes are found in classical brown adipose tissue (BAT) and in beige adipose tissue (BeAT). Similar to the control of food intake, that of BAT and BeAT thermogenesis is influenced by homeostatic signals that inform about energy reserves. BAT and BeAT are densely innervated by the sympathetic nervous system (SNS) and are under the control of brain nuclei primarily found within the hypothalamus. In addition to being modulated by the energy balance status, the control of regulatory thermogenesis is also modulated by external cues that include photoperiod, whose role in BAT and BeAT thermogenesis and metabolic activity needs to be disentangled. The photoperiod blunts the production of the pinealocyte-derived hormone melatonin, which is released in the absence of light. The brain sites and mechanisms of the thermogenic/homeostatic action of melatonin largely remains to be delineated. The overarching goal of the proposed research program is to further investigate the mechanisms whereby photoperiod and melatonin influence energy homeostasis through BAT and BeAT thermogenesis and metabolic activity. We propose to use state-of-the-art approaches, including chemogenetics and transgenesis, to target the melatonin system and disentangle the action of its various components (pinealocytes and neurons expressing melatonin receptors MT1 and MT2) on energy balance and BAT and BeAT thermogenesis and metabolic activity. Specifically, we propose (i) to delineate the effects of enhanced or repressed melatonin production from the pineal gland on the regulation of energy homeostasis and the control of BAT and BeAT thermogenesis and metabolic activity; (ii) to determine the effects of re-establishing melatonin rhythmicity on the regulation of energy homeostasis and the control of BAT and BeAT thermogenesis and metabolic activity in mice subjected to either short or long photoperiods; and (iii) to determine the brain sites and mechanisms of action of melatonin in the regulation of energy homeostasis and the control of BAT and BeAT thermogenesis and metabolic activity. We will engineer mice to control melatonin production using the chemogenetic approach referred to as Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Body composition determinations as well as indirect calorimetry measurements will be conducted. BAT or BeAT thermogenic capacity will be assessed by measuring expressions of thermogenic/metabolic genes such as Ucp1, Dio2, Pgc1a, Prdm16, Cpt1. We will use positron emission tomography/computed tomography (PET/CT) to assess the thermogenic/metabolic activity of both BAT and BeAT. The PET tracer 11C-acetate will be privileged to measure oxidative activity.