Studies on the regulation of appetite by the paraventricular nucleus of the hypothalamus

Abstract

The paraventricular nucleus of the hypothalamus (PVH) has received attention for its anorexigenic effect. Given that the PVH is heterogeneous in its neural and neuroendocrine cell populations, recent studies have utilized chemogenetic or opotogenetic approaches to identify the function of these cells in controlling appetite. As a result, progress has been made in identifying appetite suppressing and promoting cell populations within the PVH. However, these results also highlight the complex nature of the mechanisms regulating energy metabolism. In this study, I focused on two key molecules that regulate appetite and metabolism – the melanocortin-4 receptor (MC4R) and the serotonin 2C receptor (Htr2c). Through patch-clamp, I studied MC4R-relevant mechanisms involved in the metabolic side-effects of atypical antipsychotic drugs, and mechanisms for the orexigenic role of Htr2c within the PVH. Particularly, I found that risperidone, an antipsychotic drug, inhibited PVH MC4R-expressing neurons which are regarded as a pivotal in mediating satiety. Moreover, I found that the unexpected inhibitory effect of Htr2c in the PVH exhibited orexigenic effects through the Gα i/o - K ATP pathway. Furthermore, I studied the metabolic effects of Htr2c expressed by PVH corticotropin-releasing hormone (CRH) neurons. Here I demonstrated that anorexigenic effects by Htr2c agonists require downregulation of orexigenic corticosterone levels via inhibitory effects of Htr2c expressed by PVH CRH neurons. Altogether, these results suggest that MC4R-targeting drugs may alleviate metabolic disorders in patients treated with antipsychotic drugs and that understanding of the complicate mechanisms of Htr2c is required to develop effective anti-obesity drugs.