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Giuranna, J.* ; Volckmar, A.L.* ; Heinen, A.* ; Peters, T.* ; Schmidt, B.* ; Spieker, A.* ; Straub, H.* ; Grallert, H. ; Müller, T.D. ; Antel, J.* ; Haussmann, U.* ; Klafki, H.* ; Liangyou, R.* ; Hebebrand, J.* ; Hinney, A.*

The effect of SH2B1 variants on expression of leptin- and insulin-induced pathways in murine hypothalamus.

Obes. Facts 11, 93-108 (2018)
Verlagsversion DOI
Open Access Gold
Creative Commons Lizenzvertrag
Objective: We aimed to determine the effect of human SH2B1 variants on leptin and insulin signaling, which are major regulators of energy homeostasis, on the RNA level. Methods: We analyzed the expression of infrequent alleles of seven SH2B1 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. Results: 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 (p values ≤ 0.001: Gbp2b (67Cys; d = 25.11 (-3.53, -2.70)), Irf9 (689Leu; d = 44.65 (-2.57, -2.26)), and Isg15 (150Arg; d = 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 (Cap1 (150Arg; d = 7.48 (-0.62, -0.24)), Mapk1 (343Met; d = -6.80 (0.17, 0.45)), and Sorbs1 (689Leu; d = 7.82 (-1.60, -0.64))). Conclusion: The increased expression of genes in the leptin (JAK/STAT or AKT) signaling pathway implies that the main mode of action for human SH2B1 mutations might affect leptin signaling rather than insulin signaling.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Expression Genome-wide ; Gwas ; Irs ; Jak ; Locus ; Sh2b1 ; Stat; Planarian Schmidtea-mediterranea; Stem-cells; Rna-seq; Gene-expression; Regeneration; Pluripotency; Trajectories; Organism; Tissues; System
ISSN (print) / ISBN 1662-4025
e-ISSN 1662-4033
Zeitschrift Obesity Facts
Quellenangaben Band: 11, Heft: 2, Seiten: 93-108 Artikelnummer: , Supplement: ,
Verlag Karger
Verlagsort 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Begutachtungsstatus Peer reviewed