A neural basis for melanocortin-4 receptor regulated appetite Alastair S. Garfield, Chia Li, Joseph C. Madara, Bhavik P. Shah, Emily Webber, Jennifer S. Steger, John N. Campbell, Oksana Gavrilova, Charlotte E. Lee, David P. Olson, Joel K. Elmquist, Bakhos A. Tannous, Michael J. Krashes, and Bradford B. Lowell Abstract Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons are oppositely regulated by caloric depletion and co-ordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) within the paraventricular nucleus of the hypothalamus. Although this population is critical to energy balance the underlying neural circuitry remains unknown. Enabled by mice expressing Cre-recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVH MC4R neurons and further identify these cells as a functional exponent of ARC AgRP neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVH MC4R → lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVH MC4R → LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for anti-obesity drug development. Introduction The appropriate maintenance of energetic state is contingent upon the sensing of, and reaction to, homeostatic perturbation. To this end, the interoceptive awareness of caloric sufficiency and the initiation of appropriate feeding-related behaviours is in part dependent upon the central melanocortin network. This bimodal system is defined by the physiologically antagonistic actions of two non-overlapping population of neurons in the arcuate nucleus of the hypothalamus (ARC) and their opposing effects on the activity of second-order satiety-promoting neurons, presumably expressing cognate receptor isoforms. Indeed, real-time chemo- or optogenetic activation of ARC agouti-related peptide (ARC AgRP) and pro-opiomelanocortin (ARC POMC) neurons guides an increase and decrease in food intake, respectively, in a manner predicted to involve their reciprocal regulation of downstream melanocortin-4 receptor (MC4R) expressing neurons. The importance of the MC4R to energy balance regulation is supported by a wealth of pharmacological and genetic data that has clearly established its satiety-promoting and weight-loss inducing function. Perhaps most cogently, inactivating gerA neural basis for melanocortin-4 receptor regulated appetite Alastair S. Garfield, Chia Li, Joseph C. Madara, Bhavik P. Shah, Emily Webber, Jennifer S. Steger, John N. Campbell, Oksana Gavrilova, Charlotte E. Lee, David P. Olson, Joel K. Elmquist, Bakhos A. Tannous, Michael J. Krashes, and Bradford B. Lowell Abstract Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons are oppositely regulated by caloric depletion and co-ordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) within the paraventricular nucleus of the hypothalamus. Although this population is critical to energy balance the underlying neural circuitry remains unknown. Enabled by mice expressing Cre-recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVH MC4R neurons and further identify these cells as a functional exponent of ARC AgRP neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVH MC4R → lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVH MC4R → LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for anti-obesity drug development. Introduction The appropriate maintenance of energetic state is contingent upon the sensing of, and reaction to, homeostatic perturbation. To this end, the interoceptive awareness of caloric sufficiency and the initiation of appropriate feeding-related behaviours is in part dependent upon the central melanocortin network. This bimodal system is defined by the physiologically antagonistic actions of two non-overlapping population of neurons in the arcuate nucleus of the hypothalamus (ARC) and their opposing effects on the activity of second-order satiety-promoting neurons, presumably expressing cognate receptor isoforms. Indeed, real-time chemo- or optogenetic activation of ARC agouti-related peptide (ARC AgRP) and pro-opiomelanocortin (ARC POMC) neurons guides an increase and decrease in food intake, respectively, in a manner predicted to involve their reciprocal regulation of downstream melanocortin-4 receptor (MC4R) expressing neurons. The importance of the MC4R to energy balance regulation is supported by a wealth of pharmacological and genetic data that has clearly established its satiety-promoting and weight-loss inducing function. Perhaps most cogently, inactivating ger