Deciphering an AgRP-serotoninergic neural circuit in distinct control of energy metabolism from feeding

Authors: HAN, YONG - Children'S Nutrition Research Center (CNRC); XIA, GUOBIN - Children'S Nutrition Research Center (CNRC); SRISAI, DOLLADA - Vanderbilt University Medical Center; MENG, FANTAO - Children'S Nutrition Research Center (CNRC); HE, YANLIN - Children'S Nutrition Research Center (CNRC); RAN, YALI - Children'S Nutrition Research Center (CNRC); HE, YANG - Children'S Nutrition Research Center (CNRC); FARIAS, MONICA - Children'S Nutrition Research Center (CNRC); HOANG, GIANG - Children'S Nutrition Research Center (CNRC); TOTH, ISTVAN - Szent Istvan University; DIETRICH, MARCELO - Yale School Of Medicine; CHEN, MIAO-HSUEH - Children'S Nutrition Research Center (CNRC); XU, YONG - Children'S Nutrition Research Center (CNRC); WU, QI - Children'S Nutrition Research Center (CNRC)

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/10/2021
Publication Date: 6/10/2021
Citation: Han, Y., Xia, G., Srisai, D., Meng, F., He, Y., Ran, Y., He, Y., Farias, M., Hoang, G., Toth, I., Dietrich, M.O., Chen, M., Xu, Y., Wu, Q. 2021. Deciphering an AgRP-serotoninergic neural circuit in distinct control of energy metabolism from feeding. Nature Communications. 12:3525. Article https://doi.org/10.1038/s41467-021-23846-x.
DOI: https://doi.org/10.1038/s41467-021-23846-x

Interpretive Summary: This paper highlights a groundbreaking discovery for one of the major research projects that are currently developed in our lab, how the AgRP neural circuit in differential regulation of feeding and energy expenditure. This exciting story uncovers a novel mechanism about how a unique subgroup of AgRP neurons establish functional connections with the midbrain serotonin signaling system to exclusively mediate energy expenditure and basal body temperature without affecting appetite. Surprisingly, manipulation of this pathway can efficiently counter against obesity through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat. Discovery of this novel neural circuit with exclusive regulation of energy expenditure illuminates a unique framework of developing next-gen, non-appetite oriented, therapeutic approaches for obesity and metabolic disorders.

Technical Abstract: Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energ expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4RdlDRN neurons integrate pre-synaptic AgRP signaling, thereby modulating the post-synaptic serotonergic pathway. Specifically, the MC4RdlDRN signaling elicits profound, bi-directional, regulation of body weight mainly through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat while feeding remains intact. Together, we suggest that this AgRP neural circuit plays a unique role in persistent control of energy expenditure and body weight, hinting next-generation therapeutic approaches for obesity and metabolic disorders.