MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus

Significance Both in rodents and humans, melanocortin-4 receptors (MC4Rs) suppress appetite and prevent obesity. Unfortunately, the underlying neural mechanisms by which MC4Rs regulate food intake are poorly understood. Unraveling these mechanisms may open up avenues for treating obesity. In the present study we have established that MC4Rs on neurons in the paraventricular nucleus of the hypothalamus are both necessary and sufficient for MC4R control of feeding and that these neurons are glutamatergic and not GABAergic and do not express the neuropeptides oxytocin, corticotropin-releasing hormone, prodynorphin, or vasopressin. In addition, we identify downstream projections from these glutamatergic neurons to the lateral parabrachial nucleus, which could mediate the appetite suppressing effects.