These findings, together with the obesity of mice and humans with damaging mutations in Sh2b1 and in mice lacking Sh2b1 in the brain, suggest potential roles for a LepRb/SH2B1/IRS1/2 → PI3K pathway in leptin action (Doche et al. 2012; Jiang et al. 2020b). Here, LEP is linked to obesity due to melanocortin 4 receptor deficiency.