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

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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, Pgc1, 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.