Glucose and insulin induce Ca2+ signaling in nesfatin-1 neurons in the hypothalamic paraventricular nucleus

Nucleobindin-2 derived nesfatin-1 in the hypothalamic paraventricular nucleus (PVN) plays a role in inhibition of feeding. The neural pathways downstream of PVN nesfatin-1 have been extensively investigated. However, regulation of the PVN nesfatin-1 neurons remains unclear. Since starvation decreases and refeeding stimulates nesfatin-1 expression specifically in the PVN, this study aimed to clarify direct effects of meal-evoked metabolic factors, glucose and insulin, on PVN nesfatin-1 neurons. High glucose (10 mM) and insulin (10−13 M) increased cytosolic calcium concentration ([Ca2+]i) in 55 of 331 (16.6%) and 32 of 249 (12.9%) PVN neurons, respectively. Post [Ca2+]i measurement immunocytochemistry identified that 58.2% of glucose-responsive and 62.5% of insulin-responsive neurons were immunoreactive to nesfatin-1. Furthermore, a fraction of the glucose-responsive nesfatin-1 neurons also responded to insulin, and vice versa. Some of the neurons that responded to neither glucose nor insulin were recruited to [Ca2+]i increases by glucose and insulin in combination. Our data demonstrate that glucose and insulin directly interact with and increase [Ca2+]i in nesfatin-1 neurons in the PVN, and that the nesfatin-1 neuron is the primary target for them in the PVN. The results suggest that high glucose- and insulin-induced activation of PVN nesfatin-1 neurons serves as a mechanism through which meal ingestion stimulates nesfatin-1 neurons in the PVN and thereby produces satiety.

► Meal-evoked high glucose and insulin increase [Ca2+]i in PVN nesfatin-1 neurons. ► Glucose and insulin target a common subpopulation of PVN nesfatin-1 neurons. ► Glucose plus insulin recruit some unresponsive nesfatin-1 neurons to responses. ► Glucose- and insulin-activated PVN nesfatin-1 neurons may link meals to satiety.