Low blood glucose concentrations, resulting from fasting or exercise, are sensed by the central nervous system, which sends neuronal signals to pancreatic alpha cells to produce the hormone glucagon. In turn, glucagon stimulates glycogenolysis and gluconeogenesis in the liver to restore blood glucose to homeostatic levels. Šestan et al. now describe a second, indirect circuit by which the nervous system can stimulate glucagon production, via the mobilization of intestinal innate lymphoid cells (ILCs).

Compared with wild-type mice and Rag1−/− mice (which lack adaptive lymphocytes), Rag2−/−Il2rg−/− mice (which lack adaptive lymphocytes and ILCs) had reduced levels of plasma glucose after short-term and long-term fasting, associated with reduced expression of the gene encoding preproglucagon (Gcg) and low levels of glucagon hormone in the blood. Administration of exogenous glucagon increased blood glucose levels after fasting in Rag2−/−Il2rg−/− mice.