The initial cephalic phase of insulin secretion is mediated through the vagus nerve and is not due to glycemic stimulation of pancreatic β cells. Recently, IL-1β was shown to stimulate postprandial insulin secretion. Here, we describe that this incretin-like effect of IL-1β involves neuronal transmission. Furthermore, we found that cephalic phase insulin release was mediated by IL-1β originating from microglia. Moreover, IL-1β activated the vagus nerve to induce insulin secretion and regulated the activity of the hypothalamus in response to cephalic stimulation. Notably, cephalic phase insulin release was impaired in obesity, in both mice and humans, and in mice, this was due to dysregulated IL-1β signaling. Our findings attribute a regulatory role to IL-1β in the integration of nutrient-derived sensory information, subsequent neuronally mediated insulin secretion, and the dysregulation of autonomic cephalic phase responses in obesity.