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

Yong Han,Giang Hoang,Yong Xu,Marcelo O Dietrich,Qi Wu,István Tóth,Yang He,Yali Ran,Yanlin He,Dollada Srisai,Monica Farias,Fantao Meng,Guobin Xia,Miao-Hsueh Chen

doi:10.1038/s41467-021-23846-x

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.

Highlights

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
To distinguish from other AgRP projections, we found that optogenetic activation of neither the AgRP → paraventricular nucleus (PVN) feeding circuit nor the AgRP → ventrolateral periaqueductal gray circuit, which is in close proximity to the dorsal lateral part of dorsal raphe nucleus (dlDRN), exhibits any significant effect on thermogenesis (Supplementary Fig. 2c–e)
Comparing to several groups that account for critical subset of the control combination, we found that the photoinhibition of 5-HTdmDRN neurons receiving projections from MC4RdlDRN neurons suppressed the physiological thermogenesis, and blunted the enhanced thermogenesis induced by diphtheria toxin (DT) ablation of AgRPARC → dlDRN

Summary

Introduction

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. We identify an additional link by demonstrating that a subset of caudal AgRPARC neurons send inhibitory projections to MC4R neurons in the dorsal lateral part of dorsal raphe nucleus (dlDRN), which in turn send glutamatergic projections to a subset of 5-HT neurons in the dorsal medial DRN (dmDRN), thereby establishing a functional neural circuit that controls thermogenesis and energy expenditure without affecting feeding. We show that neuronal ablation and optogenetic/chemogenetic manipulation of AgRPARC → MC4RdlDRN → 5HTdmDRN circuit bidirectionally control thermogenesis and energy expenditure, but not food intake. We reveal that suppression of this neural circuit significantly reduces body weight in obese animals through restoration of mitochondrial uncoupling in brown/beige fat tissues

Methods

Results

Conclusion