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的产热也受到告知能量储备的稳态信号的影响。BAT和BeAT受交感神经系统（SNS）的密集支配，主要受下丘脑内的脑核的控制。除了受能量平衡状态的调节外，调节产热的控制还受包括光周期在内的外部信号的调节，其在BAT和BeAT产热和代谢活动中的作用需要解开。光周期减弱了松果体细胞衍生的褪黑激素的产生，褪黑激素是在没有光的情况下释放的。褪黑素的产热/稳态作用的脑部位和机制在很大程度上仍有待研究。该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，以褪黑激素系统为目标，并解开其各种成分（松果体细胞和表达褪黑激素受体MT1和MT2的神经元）在能量平衡、BAT和BeAT产热和代谢活性方面的作用。具体来说，我们建议(i)描述松果体增强或抑制褪黑激素产生对能量稳态调节以及BAT和BeAT产热和代谢活动的控制的影响；（ii）确定重建褪黑激素节律性对短期或长期光周期小鼠能量稳态调节和BAT、BeAT产热及代谢活动的控制的影响；（iii）确定褪黑素在调节能量稳态、控制BAT和BeAT产热和代谢活动中的脑部位和作用机制。我们将利用被称为设计药物特异性激活的设计受体（DREADD）的化学遗传学方法来控制褪黑激素的产生。将进行体成分测定和间接量热测定。通过测量产热/代谢基因如Ucp1、Dio2、Pgc1a、Prdm16、Cpt1的表达来评估BAT或BeAT的产热能力。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/代谢活性。PET示踪剂11c -醋酸酯将有利于测量氧化活性。

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.