Deciphering a neuronal circuit that mediates appetite

Nature. 2012 Mar 14;483(7391):594-7. doi: 10.1038/nature10899.


Hypothalamic neurons that co-express agouti-related protein (AgRP), neuropeptide Y and γ-aminobutyric acid (GABA) are known to promote feeding and weight gain by integration of various nutritional, hormonal, and neuronal signals. Ablation of these neurons in mice leads to cessation of feeding that is accompanied by activation of Fos in most regions where they project. Previous experiments have indicated that the ensuing starvation is due to aberrant activation of the parabrachial nucleus (PBN) and it could be prevented by facilitating GABA(A) receptor signalling in the PBN within a critical adaptation period. We speculated that loss of GABA signalling from AgRP-expressing neurons (AgRP neurons) within the PBN results in unopposed excitation of the PBN, which in turn inhibits feeding. However, the source of the excitatory inputs to the PBN was unknown. Here we show that glutamatergic neurons in the nucleus tractus solitarius (NTS) and caudal serotonergic neurons control the excitability of PBN neurons and inhibit feeding. Blockade of serotonin (5-HT(3)) receptor signalling in the NTS by either the chronic administration of ondansetron or the genetic inactivation of Tph2 in caudal serotonergic neurons that project to the NTS protects against starvation when AgRP neurons are ablated. Likewise, genetic inactivation of glutamatergic signalling by the NTS onto N-methyl D-aspartate-type glutamate receptors in the PBN prevents starvation. We also show that suppressing glutamatergic output of the PBN reinstates normal appetite after AgRP neuron ablation, whereas it promotes weight gain without AgRP neuron ablation. Thus we identify the PBN as a hub that integrates signals from several brain regions to bidirectionally modulate feeding and body weight.

Publication types

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

MeSH terms

  • Agouti-Related Protein / metabolism
  • Animals
  • Appetite / drug effects
  • Appetite / physiology*
  • Body Weight / drug effects
  • Feeding Behavior / drug effects
  • Feeding Behavior / physiology
  • Female
  • Glutamic Acid / metabolism
  • Hypothalamus / cytology*
  • Hypothalamus / drug effects
  • Hypothalamus / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / physiology*
  • Ondansetron / pharmacology
  • Receptors, GABA-A / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Serotonergic Neurons / drug effects
  • Serotonergic Neurons / metabolism
  • Solitary Nucleus / cytology
  • Starvation / drug therapy
  • Starvation / physiopathology
  • Starvation / prevention & control
  • Weight Gain / drug effects
  • Weight Gain / physiology
  • gamma-Aminobutyric Acid / metabolism


  • Agouti-Related Protein
  • Receptors, GABA-A
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Ondansetron
  • gamma-Aminobutyric Acid