Impact of negative energy balance on the reward brain system via leptin signaling
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Patients with Anorexia show a chronic Negative Energy Balance (i.e. reduced energy intake relative to energy expenditure). The hormone leptin regulates energy balance and related neuroendocrine functions. When the administration of this hormone is combined with an animal model of anorexia (Activity-Based Anorexia, ABA), it allows for the investigation of the effects of leptin on AN-like symptoms. This study aims at assessing whether and how pharmacologic treatment with leptin can suppress or prevent the development of anorectic behaviours in ABA. Additionally, we investigated whether chemogenetic manipulations of LepR in the lateral hypothalamus (LHLepR) could be effective to modulate energy balance. To this end, in our first experiments, we will use C57BL/6J mice to determine how systemic leptin treatment impacts negative energy balance. In our last experiment, we will use the transgenic LepR-cre mouse for the same purpose, by chemogenetic manipulating LHLepR neurons. We found that following systemic and chronic leptin treatment, both aspects of energy balance (i.e. energy expenditure, and energy intake) decrease. Furthermore, chronic and systemic leptin treatment once AN-like symptoms had already developed, can prevent a drop in food intake as well as an increase in energy expenditure. Finally, Chemogenetic manipulation of hM3DGi in LHLepR neurons does not lead to reduced FAA or impact on BW/FI. Leptin treatment in ABA negatively influenced energy balance by decreasing RWA, but at the same time negatively influenced energy balance by decreasing food intake. Furthermore, once AN-like symptoms had already developed, leptin treatment did not negatively affect food intake while suppressing the emergence of hyperactivity during the initial phase of the leptin treatment. Finally, Chemogenetic stimulation of hM3DGi in LHLepR neurons does not lead to a reduction in hyperactive behaviours, while contemporarily preventing the emergence of significant differences in body weight or food intake in CNO vs vehicle mice.