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

Yong Han, Guobin Xia, Dollada Srisai, Fantao Meng, Yanlin He, Yali Ran, Yang He, Monica Farias, Giang Hoang, István Tóth, Marcelo O. Dietrich, Miao-Hsueh Chen, Yong Xu and Qi Wu ()
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Yong Han: USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine
Guobin Xia: USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine
Dollada Srisai: Vanderbilt University School of Medicine
Fantao Meng: USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine
Yanlin He: USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine
Yali Ran: USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine
Yang He: USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine
Monica Farias: USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine
Giang Hoang: USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine
István Tóth: Szent Istvan University
Marcelo O. Dietrich: Yale University School of Medicine
Miao-Hsueh Chen: USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine
Yong Xu: USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine
Qi Wu: USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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 energy 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.

Date: 2021
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DOI: 10.1038/s41467-021-23846-x

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