Thursday, July 19, 2012
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
and AGRP [c]. The
peptide and protein are both known to increase food intake.
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.
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.)