Figure 1. Model for processes mediated by FOXO1 in AGRP neurons. Researchers have now elucidated the role of forkhead box O1 (FOXO1) transcription factor signaling in hypothalamic neurons that express agouti related protein (AGRP). In the process, the researchers identified G protein-coupled receptor 17 (GPR17) as a potential therapeutic target to help control obesity.

(I) In AGRP neurons with functional FOXO1, activation of GPR17 increases food intake [a]. This is thought to occur via modulation of downstream ion channels [b] in a manner that stimulates the release of neuropeptide Y (NPY) and AGRP [c]. The peptide and protein are both known to increase food intake.

Antagonizing GPR17 has the opposite effects.

(II) Knocking out FOXO1 in AGRP neurons decreases the expression of GPR17 [a] and leads to less food intake than normal FOXO1 expression. Loss of the transcription factor also improves glucose homeostasis, increases sensitivity to insulin and leptin [b] and leads to greater lean body mass.

At this time, it is not known whether GPR17 antagonism itself will increase glucose homeostasis, body leanness and sensitivity to leptin and insulin. (Figure based on Figure 7G in ref. 1.)