TY - JOUR
T1 - FoxO1 target Gpr17 activates AgRP neurons to regulate food intake
AU - Ren, Hongxia
AU - Orozco, Ian J.
AU - Su, Ya
AU - Suyama, Shigetomo
AU - Gutiérrez-Juárez, Roger
AU - Horvath, Tamas L.
AU - Wardlaw, Sharon L.
AU - Plum, Leona
AU - Arancio, Ottavio
AU - Accili, Domenico
N1 - Funding Information:
H.R. is the recipient of a mentor-based postdoctoral fellowship from the American Diabetes Association. This work was supported by NIH grants DK58282 and DK57539 (D.A.), DK80003 (S.L.W.), DK45024 (R.G.-J.), NS49442 (O.A.), DK080000 and OD006850 (T.L.H.), and DK63608 (Columbia University Diabetes Research Center). We thank Ms. Taylor Y. Lu and Kana Meece for excellent technical support, and we thank members of the Accili laboratory for critical discussion of the data.
PY - 2012/6/8
Y1 - 2012/6/8
N2 - Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity.
AB - Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity.
UR - http://www.scopus.com/inward/record.url?scp=84861976352&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861976352&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.04.032
DO - 10.1016/j.cell.2012.04.032
M3 - Article
C2 - 22682251
AN - SCOPUS:84861976352
SN - 0092-8674
VL - 149
SP - 1314
EP - 1326
JO - Cell
JF - Cell
IS - 6
ER -
