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. Neurons within the brainstem dorsal vagal complex (DVC) receive direct information from the digestive system and project to second-order regions in the brain to regulate food intake. Although γ-aminobutyric acid is expressed in the DVC (GABA^DVC), its function in this region has not been defined. In order to discover the unique gene expression signature of GABA^DVC cells, we used single-nucleus RNA sequencing (Nuc-seq), and this revealed 19 separate clusters. We next probed the function of GABA^DVC cells and discovered that the selective activation of GABA^DVC neurons significantly controls food intake and body weight. Optogenetic interrogation of GABA^DVC circuitry identified GABA^DVC → hypothalamic arcuate nucleus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed that GABA^DVC → ARC stimulation inhibits hunger-promoting neuropeptide Y (NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABA^DVC → ARC circuit curbs food intake. These data identify GABA^DVC as a new modulator of feeding behavior and body weight and a controller of orexigenic NPY neuron activity, thereby providing insight into the neural underpinnings of obesity.

Keywords: body weight; dorsal vagal complex; food intake; gamma-aminobutyric acid; hunger; hypothalamus; neuropeptide Y; nucleus of the solitary tract; obesity.