The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus.

<bold><italic>Objective: </italic></bold>We aimed to determine the effect of human <italic>SH2B1</italic> variants on leptin and insulin signaling, which are major regulators of energy homeostasis, on the RNA level. <bold><italic>Methods:</italic></bold> We analyzed the expression of infrequent alleles of seven <italic>SH2B1</italic> variants (Arg67Cys, Lys150Arg, Thr175Ala, Thr343Met, Thr484Ala, Ser616Pro, and Pro689Leu) in response to insulin or leptin cell stimulation. Two of these were identified in own mutation screens, the others were predicted to be deleterious or to serve as controls. The variants were analyzed in a homologous system of mouse hypothalamic cells. Changes in expression of downstream genes were measured. Student's t-test for independent samples was applied, and effect sizes using Cohen's d with 95% confidence intervals were therefore calculated. <bold><italic>Results:</italic></bold> In 34 of 54 analyzed genes involved in leptin (JAK/STAT or AKT) signaling, variants nominally changed expression. The expression of three genes was considerably increased <italic>(</italic>p values ≤ 0.001: <italic>Gbp2b</italic> (67Cys; <italic>d</italic> = 25.11 (-3.53, -2.70)), <italic>Irf9</italic> (689Leu; <italic>d</italic> = 44.65 (-2.57, -2.26)), and <italic>Isg15</italic> (150Arg; <italic>d</italic> = 20.35 (-2.19, -1.57))). Of 32 analyzed genes in the insulin signaling pathway, the expression of 10 genes nominally changed (p ≤ 0.05), three resulted in p values ≤ 0.01 (<italic>Cap1</italic> (150Arg; <italic>d</italic> = 7.48 (-0.62, -0.24)), <italic>Mapk1</italic> (343Met; <italic>d</italic> = -6.80 (0.17, 0.45)), and <italic>Sorbs1</italic> (689Leu; <italic>d</italic> = 7.82 (-1.60, -0.64))). <bold><italic>Conclusion:</italic></bold> The increased expression of genes in the leptin (JAK/STAT or AKT) signaling pathway implies that the main mode of action for human <italic>SH2B1</italic> mutations might affect leptin signaling rather than insulin signaling. [ABSTRACT FROM AUTHOR]