JAK2 phosphorylates IRS1/2 after IRS1/2 binds SH2B1 in the LEP:LEPR:JAK2:SH2B1 complex (Martin-Romero and Sanchez-Margalet 2001, Li et al. 2007). However, in some cells leptin may only affect phosphorylation of IRS1/2 when insulin signaling subsequently occurs (Szanto and Kahn 2000). As inferred from mouse and rat (Buettner et al. 2008, Hill et al. 2008) phosphorylated IRS1/2 then activates PI3K independently of STAT3 signaling.