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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 PMC
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
Sprache englisch
Veröffentlichungsjahr 2018
HGF-Berichtsjahr 2018
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
Institut(e) Institute of Epidemiology (EPI)
Institute of Diabetes and Obesity (IDO)
POF Topic(s) 30202 - Environmental Health
90000 - German Center for Diabetes Research
Forschungsfeld(er) Genetics and Epidemiology
Helmholtz Diabetes Center
PSP-Element(e) G-504091-002
G-501900-402
G-501900-221
DOI 10.1159/000486962
WOS ID WOS:000432742400002
Scopus ID 85045295290
PubMed ID 29631267
Erfassungsdatum 2018-07-11
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