Leptin-inhibited PBN neurons enhance counter-regulatory responses to hypoglycemia in negative energy balance

Hypoglycemia initiates the counter regulatory response (CRR), in which the sympathetic nervous system, glucagon, and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin restrains energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here, we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates leptin receptor (LepRb) and cholecystokinin (CCK)-expressing neurons of the parabrachial nucleus (PBN), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells and Cck(cre)-mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, while their activation mimics the CRR in a CCK-dependent manner. PBN LepRb(CCK) neurons represent a crucial component of the CRR system, and may represent a therapeutic target in hypoglycemia.