Loss of GABAergic transmission from somatostatin neurons leads to starvation, which is attenuated by a palatable diet.

Somatostatin (SST)-expressing neurons are predominantly inhibitory and co-release the fast-acting neurotransmitter γ-aminobutyric acid (GABA). However, the role of GABAergic transmission from SST neurons remains incompletely understood. Here, we showed that mice with inactivation of the gene encoding the vesicular GABA transporter (VGAT) specifically in SST-expressing cells exhibited decreased food intake, weight loss, and hypoglycemia, despite increased activity of orexigenic agouti-related protein-expressing neurons, and died before reaching 4 weeks of age. Additionally, loss of GABAergic transmission from SST neurons led to overactivation of brainstem areas that induce meal termination and anorexia, including the nucleus of the solitary tract and the lateral parabrachial nucleus (PBN), particularly calcitonin gene-related peptide-expressing neurons. Remarkably, when SST-specific VGAT knockout mice were exposed to a highly palatable diet, their precocious death was partially prevented. The exclusive source of SST innervation to the PBN was from neurons of the lateral central nucleus of the amygdala (CEA) and the oval subdivision of the bed nucleus of the stria terminalis (BNST). Furthermore, CEASST and BNSTSST neurons exhibited distinct neurochemical identities and connectivity compared with protein kinase C-δ neurons. In conclusion, GABAergic transmission from SST neurons is essential for postnatal survival and regulates the activity of key neurocircuits that control food intake.