Integration of Lepr circuits for thermoregulation and energy status

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Despite intense obesity research and growing knowledge of central and peripheral mechanisms that modulate food intake and energy expenditure, lifestyle interventions to treat obesity have been consistently unsuccessful in the long-term. Powerful physiological adaptations to fasting and food restriction oppose weight loss and are thought to be the culprit that prevents long-term maintenance of weight loss. Yet, our understanding of these physiological adaptations and the neuronal circuits involved is insufficient. Our work on leptin responsive neurons in the hypothalamus (POALepr and DMHLepr neurons) has indicated that temperature sensing and energy sensing integrate in the same neuronal circuits that modulate energy expenditure (EE) and food intake (FI). Furthermore, our data indicate that EE and FI are regulated independent circuits. In line with this, we show compelling evidence that temperature and energy state greatly impact each other due to explicit changes in neuronal activity within these circuits. Our working hypothesis integrates known energy sensing circuits with temperature sensing circuits and highlights important changes in leptin sensitivity that are not only impacted by energy sensing but also with ambient temperature, highlighting leptin resistance as a physiological, rather than pathological condition. This novel view is an important progress for our understanding of physiological adaptations that will be important for human and animal studies of metabolism in health and disease. The proposed experiments focus on the neuronal circuit integration of temperature-dependent and energy state dependent changes in EE and FI. In Aim 1 we will investigate warm-sensing POALepr neurons that project to the DMH and their role to suppress EE via cold-sensing DMHLepr. Furthermore, we will show that cold-sensing DMHLepr are also regulated by energy sensing ARC neurons. In Aim 2 we will investigate warm-sensing POALepr neurons that project to the ARC and their role to suppress FI via anorexigenic ARCPOMC neurons. In Aim 3 we will investigate the role of leptin and dynamic changes in leptin sensitivity to selectively regulate EE via DMH-projecting Lepr neurons, while FI is regulated via PVN projecting Lepr neurons.