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

松果体细胞衍生的褪黑激素对能量稳态自主调节的作用

• 批准号: RGPIN-2020-06371
• 负责人: Richard, Denis
• 金额: $ 2.4万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=741172
• 关键词: Role; Pinealocyte; Derived; Melatonin; Autonomic

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.

能量平衡(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作用。棕色脂肪细胞存在于经典的棕色脂肪组织(BAT)和米色脂肪组织(BAT)中。与食物摄入量的控制类似，蝙蝠和节拍的生热作用也受到有关能量储备的动态平衡信号的影响。蝙蝠和节拍由交感神经系统(SNS)密集支配，并受主要位于下丘脑的脑核控制。除了受到能量平衡状态的调节外，调控产热的调控还受到包括光周期在内的外部信号的调控，光周期在蝙蝠和节拍的产热和代谢活动中的作用需要解开。光周期使松果体细胞衍生的激素褪黑素的产生变得迟钝，褪黑素在没有光线的情况下释放。褪黑素的生热/稳态作用的大脑部位和机制在很大程度上仍有待描述。拟议研究计划的总体目标是进一步研究光周期和褪黑素通过蝙蝠和节拍产热和代谢活动影响能量动态平衡的机制。我们建议使用最先进的方法，包括化学遗传学和转基因，靶向褪黑素系统，并解开其各种成分(松果体细胞和表达褪黑素受体MT1和MT2的神经元)在能量平衡和BAT和BAT的产热和代谢活动中的作用。具体地说，我们建议(I)描述松果体褪黑素的增加或抑制对能量平衡的调节以及对BAT和BAT的产热和代谢活动的控制的影响；(Ii)确定重建褪黑素的节律性对短光或长光周期下小鼠能量平衡的调节和BAT和BAT和BAT的产热和代谢活动的影响；(Iii)确定褪黑素在调节能量平衡和控制BAT和BAT和BAT的产热和代谢活动中的大脑部位和作用机制。我们将利用化学遗传学的方法设计小鼠来控制褪黑激素的产生，这种方法被称为由设计药物独有激活的设计受体(DREADD)。将进行身体成分测定以及间接量热法测量。BAT或BAT的生热能力将通过测量Ucp1、Dio2、PGC1a、Prdm16、Cpt1等生热/代谢基因的表达来评估。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BAT的产热/代谢活动。PET示踪剂11C-醋酸酯将有特权测量氧化活性。