A neural basis for melanocortin-4 receptor regulated appetite
Shah, Bhavik P.
Steger, Jennifer S.
Lee, Charlotte E.
Elmquist, Joel K.
Krashes, Michael J.
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CitationGarfield, A. S., C. Li, J. C. Madara, B. P. Shah, E. Webber, J. S. Steger, J. N. Campbell, et al. 2015. “A neural basis for melanocortin-4 receptor regulated appetite.” Nature neuroscience 18 (6): 863-871. doi:10.1038/nn.4011. http://dx.doi.org/10.1038/nn.4011.
AbstractPro-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 PVHMC4R neurons and further identify these cells as a functional exponent of ARCAgRP neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVHMC4R→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 PVHMC4R→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for anti-obesity drug development.
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