FoxO1 target Gpr17 activates AgRP neurons to regulate food intake.
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.
Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
Hongxia
H
Ren
Ian J
IJ
Orozco
Ya
Y
Su
Shigetomo
S
Suyama
Roger
R
Gutiérrez-Juárez
Tamas L
TL
Horvath
Sharon L
SL
Wardlaw
Leona
L
Plum
Ottavio
O
Arancio
Domenico
D
Accili
D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004435:Eating; D004734:Energy Metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C534979:GPR17 protein, mouse; D020738:Leptin; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D005947:Glucose