GCG and obesity due to melanocortin 4 receptor deficiency: We showed that 1) GLP-1 regulates PVNGLP-1R→DVC glutamate release via the PKA pathway in the presynaptic compartment (Fig. 1); 2) ablation of GLP-1R in the presynaptic neurons in the PVNGLP-1R→DVC circuit causes obesity (Fig. 5a–c); 3) blockade of synaptic transmission in the PVNGLP-1R→DVC circuit causes obesity and glucose metabolism deficits (Fig. 5d–m).