Deciphering an AgRP-Serotoninergic Neural Circuit in Distinct Control of Energy Metabolism From Feeding

Authors

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
Qi Wu

Publication Date

6-10-2021

Journal

Nature Communications

DOI

10.1038/s41467-021-23846-x

PMID

34112797

PMCID

PMC8192783

PubMedCentral® Posted Date

6-10-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Adipose Tissue, Beige, Adipose Tissue, Brown, Agouti-Related Protein, Animals, Body Weight, Chromatography, Liquid, Eating, Energy Metabolism, Hypothalamus, Male, Mice, Neural Conduction, Obesity, Optogenetics, Receptor, Melanocortin, Type 4, Serotonergic Neurons, Serotonin, Signal Transduction, Tandem Mass Spectrometry, Temperature, Neural circuits, Metabolism, Neurophysiology

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.