Insulin binds to its receptor on POMC and AgRP neurons, stimulating receptor autophosphorylation and activating its signal cascade. IRS proteins bind to the phosphorylated residues on the IR and subsequently recruit the regulatory subunit p85 of PI3K. PI3K thereby becomes activated and phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP₂) on position 3′ in the inositol ring, generating PIP₃. The lipid phosphatase PTEN antagonizes this by dephosphorylating PIP₃ to generate PIP₂. The protein kinase B/AKT and phosphoinositide-dependent protein kinase 1 (PDK1) bind to PIP₃ via their pleckstrin homology (PH) domains. AKT is readily phosphorylated and activated by PDK1. Phosphorylated AKT enters the nucleus, where it phosphorylates FOXO1. This leads to exclusion from the nucleus and thereby to inactivation of FOXO1. FOXO1 exerts different effects in POMC and AgRP neurons. In POMC neurons, it diminishes POMC transcription by recruiting Ncor and Hdac1 and by competing with binding sites for phosphorylated STAT3 in the promoter. By phosphorylating and excluding FOXO1 from the nucleus, insulin de-inhibits the promoter, thereby increasing POMC expression. In AgRP neurons, FOXO1 increases AgRP transcription. Here insulin decreases FOXO1-mediated transcription of AgRP by excluding FOXO1 from the nucleus. Leptin binds to its receptor, leading to recruitment of JAKs, which phosphorylate the receptor. The STAT3 monomer binds to the activated leptin receptor and is phosphorylated by JAKs. Upon phosphorylation, two STATs homodimerize and translocate to the nucleus, where they activate POMC transcription in POMC neurons and decrease AgRP transcription in AgRP neurons. It is possible that leptin also induces activation of PI3K. Consequently, insulin de-inhibits and leptin activates the POMC promoter. Insulin deactivates and leptin inhibits the AgRP promoter.