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

• Published in: Obesity facts Vol. 11; no. 2; pp. 93 - 108
• Main Authors: Giuranna, Johanna, Volckmar, Anna-Lena, Heinen, Anna, Peters, Triinu, Schmidt, Börge, Spieker, Anne, Straub, Helena, Grallert, Harald, Müller, Timo D., Antel, Jochen, Haußmann, Ute, Klafki, Hans, Rui, Liangyou, Hebebrand, Johannes, Hinney, Anke
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2018; S. Karger GmbH; Karger Publishers
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adolescent; Adult; Age; Animals; Body Weight - drug effects; Body Weight - genetics; Cells, Cultured; Cloning; Expression genome-wide; Female; Gene Expression Regulation - drug effects; Genes; Growth factors; GWAS; Homeostasis; Humans; Hypothalamus; Hypothalamus - drug effects; Hypothalamus - metabolism; Insects; Insulin - metabolism; Insulin - pharmacology; Insulin resistance; IRS; JAK; Kinases; Leptin - metabolism; Leptin - pharmacology; Locus; Male; Mice; Mice, Knockout; Mutation; Obesity; Research Article; Rodents; SH2B1; Signal Transduction - drug effects; Signal Transduction - genetics; Standard deviation; STAT; Young Adult; United States > US; Germany; STAT; Expression genome-wide; GWAS; JAK; IRS; Locus; SH2B1
• ISSN: 1662-4025; 1662-4033
• DOI: 10.1159/000486962

Objective: We aimed to determine the effect of human SH2B1 variants on leptin and insulin signaling, 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 were 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), Irf9 (689Leu; d = 44.65) and Isg15 (150Arg; d = 20.35)). 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), Mapk1(343Met; d = –6.80) and Sorbs1 (689Leu; d = 7.82)). Conclusion: The increased expression of genes in leptin (JAK/STAT or AKT) signaling implies that the main mode of action for human SH2B1 mutations might affect leptin signaling rather than insulin signaling.