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

Nat Commun. 2021 Jun 10;12(1):3525. doi: 10.1038/s41467-021-23846-x.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipose Tissue, Beige / metabolism
  • Adipose Tissue, Brown / metabolism
  • Agouti-Related Protein / metabolism*
  • Animals
  • Body Weight
  • Chromatography, Liquid
  • Eating / physiology
  • Energy Metabolism / genetics
  • Energy Metabolism / physiology*
  • Hypothalamus / metabolism*
  • Male
  • Mice
  • Neural Conduction / drug effects
  • Neural Conduction / physiology*
  • Neural Conduction / radiation effects
  • Obesity / metabolism
  • Optogenetics
  • Receptor, Melanocortin, Type 4 / genetics
  • Receptor, Melanocortin, Type 4 / metabolism
  • Serotonergic Neurons / drug effects
  • Serotonergic Neurons / physiology*
  • Serotonergic Neurons / radiation effects
  • Serotonin / metabolism
  • Serotonin / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Tandem Mass Spectrometry
  • Temperature


  • Agouti-Related Protein
  • MC4R protein, mouse
  • Receptor, Melanocortin, Type 4
  • Serotonin