State-dependent central synaptic regulation by GLP-1 is essential for energy homeostasis.

Central nervous system (CNS) control of metabolism plays a pivotal role in maintaining energy homeostasis. Glucagon-like peptide-1 (GLP-1, encoded by Gcg), secreted by a distinct population of neurons located within the nucleus tractus solitarius (NTS), suppresses feeding through projections to multiple brain targets(1-3). Although GLP-1 analogs are proven clinically effective in treating type 2 diabetes and obesity(4), the mechanisms of GLP-1 action within the brain remain unclear. Here, we investigate the involvement of GLP-1 receptor (GLP-1R) mediated signaling in a descending circuit formed by GLP-1R neurons in the paraventricular hypothalamic nucleus (PVN(GLP-1R)) that project to dorsal vagal complex (DVC) neurons of the brain stem in mice. PVN(GLP- 1R)→DVC synapses release glutamate that is augmented by GLP-1 via a presynaptic mechanism. Chemogenetic activation of PVN(GLP-1R)→DVC neurons suppresses feeding. The PVN(GLP-1R)→DVC synaptic transmission is dynamically regulated by energy states. In a state of energy deficit, synaptic strength is weaker but is more profoundly augmented by GLP-1R signaling compared to an energy-replete state. In an obese state, the dynamic synaptic strength changes in the PVN(GLP-1R)→DVC descending circuit are disrupted. Blocking PVN(GLP-1R)→DVC synaptic release or ablation of GLP-1R in the presynaptic compartment increases food intake and causes obesity, elevated blood glucose, and impaired insulin sensitivity. These findings suggest that the state-dependent synaptic plasticity in this PVN(GLP-1R)→DVC descending circuit mediated by GLP-1R signaling is an essential regulator of energy homeostasis.