A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding
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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 γ-Aminobutyric acid is widely expressed in the NTS (GABA NTS ), 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 GABA NTS cells, revealing that selective activation of GABA NTS neurons significantly controls food intake and body weight. Optogenetic interrogation of GABA NTS circuitry identified GABA NTS →arcuate nucleus of the hypothalamus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed GABA NTS →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 GABA NTS →ARC circuit induces satiety. These data identify GABA NTS 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.
Highlights
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Nucleus of the solitary tract (NTS) GABA neurons are responsive to nutritional status.
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Chemogenetic GABA NTS neuron activation reduces food intake and body weight.
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GABA NTS projections to the hypothalamic arcuate nucleus (ARC) promote satiety.
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Optogenetic GABA NTS →ARC stimulation inhibits orexigenic AgRP/NPY neurons.
In Brief
Martinez 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.