A population of hypothalamic neurons expressing the Agouti-related peptide (AgRP) has been shown to be important in the induction of feeding. Although the hormones leptin and insulin act on these neurons, knocking out either leptin or insulin signaling in AgRP neurons does not seem to affect energy homeostasis. Now, Hongxia Ren et al. show that disabling both these pathways in mice by knocking out a central transcriptional mediator, FoxO1, in AgRP neurons can improve metabolism, resulting in lean mice that eat less (Cell 149, 1314–1326).

The researchers then performed microarray analyses of the AgRP hypothalamic neurons with or without FoxO1 and found that the G-coupled protein receptor Gpr17 was downregulated in FoxO1-deficient neurons. In cell culture studies, they found that FoxO1 directly bound the Gpr17 gene and increased its expression. When they administered Gpr17 agonists into the brain ventricles of mice, this increased feeding. A Gpr17 antagonist decreased feeding, suggesting that targeting this pathway could be used to treat obesity in humans.