Characterization of Kiss1 neurons as mediators of the reproductive regulation of energy balance

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ABSTRACT Reproduction and metabolism are closely regulated to ensure the survival of the organism and the species. The central control of energy balance depends on the intricate interaction of central and peripheral signals that ultimately regulate food intake and energy expenditure (EE). Among the central signals involved in the control of energy balance, melanocortins (a-MSH) produced by proopiomelanocortin (POMC) neurons play a critical role inducing satiety and increasing EE. a-MSH binds the melanocortin receptor 4 (MC4R) at the level of the paraventricular nucleus to induce satiety, however, the site of action of melanocortins to regulate EE remains under-characterized. Recently, the reproductive neuropeptide kisspeptin, encoded by Kiss1, has been identified as a metabolic factor in several animal models, for example, kisspeptin signaling deficient mice develop obesity. Kisspeptin has been demonstrated to be essential for the activation of the reproductive axis, however, its role in metabolism requires further investigation. Our preliminary data expands on these findings and suggest that melanocortin signaling to Kiss1 neurons is involved in the control of EE. We have showed that Kiss1 neurons a) express MC4R, b) respond directly to the stimulation by a-MSH, c) are direct targets of POMC neurons, which post-synaptically regulate Kiss1 neurons, and d) innervate and activate Lepr neurons in the dorsomedial hypothalamus (DMH) through glutamate release. In addition, we have demonstrated that the specific removal of MC4R from Kiss1 neurons induces an increase in body weight (BW) due to a decrease in EE without changes in overall food intake or activity and without causing hypogonadism. Therefore, we hypothesize that Kiss1 neurons serve as mediators of the melanocortin action to regulate EE through the control of LeprDMH neurons, thus uncovering a novel pathway of action for melanocortins in the control of energy balance that links reproduction and metabolism. We propose to 1) evaluate the changes in EE after ablation or chronic activation of Kiss1 neurons; 2) assess the overall contribution of Kiss1 neurons to the melanocortin regulation of EE through the re-insertion of MC4R in Kiss1 neurons of MC4RKO mice; 3) map the neurocircuitry underlying this role through the identification of neuronal projections and optogenetic activation of Kiss1 neuron terminals; 3) assess the contribution of kisspeptin co-transmitters in the control of EE. Kiss1 neurons are the nodal regulatory center of reproductive function and are, therefore, sensitive to changes in the circulating levels of sex steroids. Thus, the successful completion of this proposal may offer the first approach to a comprehensive pathway linking reproductive status and the regulation of energy expenditure that could explain the frequently observed increase in BW after menopause in women or men with low testosterone. Moreover, the characterization of Kiss1 neurons as an active player in the control of energy balance will inform the development of new strategies to improve the treatment of metabolic disorders.