Neurally distributed melanocortinergic control of energy expenditure

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DESCRIPTION (provided by applicant): Due to increasing rates of obesity and its comorbidities, there is tremendous interest in the central nervous system (CNS) control of energy balance. This basic science interest is guided in part by the need to develop effective drugs for the overweight and obese patient. Despite a large literature, our understanding of the circuits and neurochemical receptors that mediate energy balance is still limited. The proposed studies address this limitation by defining the neural circuits that mediate melanocortin's effects on energy expenditure. Disruption in CNS melanocortin receptor (MCR) signaling is the single largest monogenic cause of human obesity. Similarly, animals with disrupted MCR signaling ingest more food and expend less energy. The contribution of MCRs to energy intake control has been investigated intensely. However, much less attention is directed at defining the MCR-containing neural circuits that contribute to energy expenditure. Attention is needed, in part, because the potential contribution of MCR bearing nuclei in different brain regions to energy expenditure is largely unexplored. On the one hand, forebrain ventricular application of MCR agonists, the most common method of delivery, triggers sympathetically mediated expenditure responses that have been attributed to signaling at hypothalamic structures (e.g., the arcuate and paraventricular nuclei). On the other hand, caudal flow of the injected ligands in cerebral spinal fluid makes ligand available to extrahypothalamic sites. Given the widespread distribution of MCRs it is impossible to define which MCR-bearing neurons - among them several hypothalamic and caudal brainstem nuclei- contribute to the observed effects. The aims of my proposal address these limitations. Aim I distinguishes the respective contributions of the hypothalamic and caudal brainstem divisions of the melanocortin system to energetic control under baseline conditions by physiological, as well as neuroanatomical assessments. Aim II uses antagonist treatments to evaluate endogenous melanocortin contributions to the thermogenic responses driven by energy challenges (i.e. cold and diet). The aims use different research strategies - pharmacological, physiological and neuroanatomical - to provide the data needed to critically evaluate the hypothesis that the melanocortin system's contribution to energy expenditure is distributed across spatially distinct regions of the brain.