Melanocortin-3 receptor expression in AgRP neurons is required for normal activation of the neurons in response to energy deficiency

The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on agouti-related protein (AgRP) nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. However, MC3R knockout (KO) mice also exhibit defective behavioral and neuroendocrine responses to fasting. Here, we demonstrate that MC3R KO mice exhibit defective activation of AgRP neurons in response to fasting, cold exposure, or ghrelin while exhibiting normal inhibition of AgRP neurons by sensory detection of food in the ad libitum-fed state. Using a conditional MC3R KO model, we show that the control of AgRP neuron activation by fasting and ghrelin requires the specific presence of MC3R within AgRP neurons. Thus, MC3R is a crucial player in the responsiveness of the AgRP soma to both hormonal and neuronal signals of energy need. [Display omitted] •MC3R is required for normal AgRP neuron activation by fasting, cold, or ghrelin•MC3R in AgRP neurons is required for activation of the neurons by fasting or ghrelin•MC3R in AgRP neurons regulates genes involved in hormonal and neuronal activation Gui et al. reveal the role of MC3R in appetite control by regulating the activation of AgRP neurons in response to diverse signals of energy deficiency. Much of this effect involves a direct role of MC3R in the AgRP neuron.