Vagal activation inhibits insulin release through neuronal nitric oxide synthase in obese male mice.

The vagus nerve connects the brain and pancreas and enhances postprandial endocrine secretion from the pancreas through cholinergic signaling, such as increasing insulin release immediately after food intake in the cephalic-phase insulin response (CPIR). Here, we investigated how obesity affects vagal regulation of pancreatic endocrine function using designer receptors exclusively activated by designer drugs (DREADDs) to manipulate vagal activity. As expected, the plasma concentration of insulin was increased by vagal activation in mice expressing the excitatory DREADD hM3Dq (M3 mice) and decreased by vagal inactivation in mice expressing inhibitory DREADD hM4Di (M4 mice). However, vagal activation in M3 mice with diet-induced obesity did not elicit an early increase in insulin and instead produced a delayed insulin decrease. Mathematical modeling showed that plasma insulin dynamics in these mice were best explained by a model incorporating both the insulin-increasing and insulin-decreasing effects of the vagus nerve. Furthermore, the insulin-decreasing effect was mediated by nitric oxide (NO)-dependent, noncholinergic signaling and was enhanced in obesity. In obese M3 mice, vagal deficiency of neuronal NO synthase (nNOS) abolished the insulin-decreasing effect and restored insulin release after vagal activation. Vagal nNOS deficiency also enhanced insulin release after voluntary feeding, consistent with the CPIR. These findings suggest that vagal NO action inhibits postprandial insulin release, particularly in obesity.