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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760601
• 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。能量消耗由多种组成部分组成，其中包括棕色脂肪细胞调节生热作用。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 生热作用也受到有关能量储备的稳态信号的影响。 BAT 和 BeAT 受到交感神经系统 (SNS) 的密集支配，并受主要位于下丘脑内的脑核的控制。 除了受到能量平衡状态的调节外，调节产热的控制还受到包括光周期在内的外部因素的调节，光周期在 BAT 和 BeAT 产热和代谢活动中的作用需要阐明。光周期会减弱松果体细胞衍生的褪黑激素的产生，这种激素在没有光的情况下会释放。褪黑素生热/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技术，来靶向褪黑激素系统，并解开其各个成分（松果体细胞和表达褪黑激素受体 MT1 和 MT2 的神经元）对能量平衡以及 BAT 和 BeAT 产热和代谢活动的作用。具体来说，我们建议 (i) 描述松果体褪黑激素产生增强或抑制对能量稳态调节以及 BAT 和 BeAT 产热和代谢活动控制的影响； (ii) 确定在短光周期或长光周期下重建褪黑激素节律对能量稳态调节以及 BAT 和 BeAT 生热作用和代谢活动控制的影响； (iii) 确定褪黑激素在调节能量稳态以及控制 BAT 和 BeAT 产热和代谢活动中的大脑部位和作用机制。我们将使用被称为设计药物独家激活的设计受体（DREADD）的化学遗传学方法对小鼠进行基因改造来控制褪黑激素的产生。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（例如 Ucp1、Dio2、Pgc1a、Prdm16、Cpt1）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 的生热/代谢活性。 PET 示踪剂 11C-醋酸盐将有幸测量氧化活性。