A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding

Abstract

The obesity epidemic is principally driven by the consumption of more calories than the body requires. It is therefore essential that the mechanisms underpinning feeding behavior are defined. The brainstem nucleus of the solitary tract (NTS) receives direct information from the digestive system and projects to second order regions in the brain. Though {gamma}-Aminobutyric acid is widely expressed in the NTS (GABANTS), its function has not been defined. Characterization of GABA cells using single nucleus RNA sequencing (Nuc-Seq) identified at least 19 clusters. Here we provide insight into the function of GABANTS cells, revealing that selective activation of GABANTS neurons significantly controls food intake and body weight. Optogenetic interrogation of GABANTS circuitry identified GABANTS[->]arcuate nucleus of the hypothalamus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed GABANTS[->]ARC stimulation inhibits hunger promoting agouti-related protein/neuropeptide Y (AgRP/NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABANTS[->]ARC circuit induces satiety. These data identify GABANTS as a new modulator of feeding behavior, body weight and controller of orexigenic AgRP/NPY activity, thereby providing insight into the neural underpinnings of obesity. HighlightsO_LINucleus of the solitary tract (NTS) GABA neurons are responsive to nutritional status. C_LIO_LIChemogenetic GABANTS neuron activation reduces food intake and body weight. C_LIO_LIGABANTS projections to the hypothalamic arcuate nucleus (ARC) promote satiety. C_LIO_LIOptogenetic GABANTS[->]ARC stimulation inhibits orexigenic AgRP/NPY neurons. C_LI In BriefMartinez de Morentin et al. identify GABAergic neurons in the nucleus of the solitary tract as a new player in the circuit governing feeding behavior and body weight.