Human SH2B1 mutations are associated with maladaptive behaviors and obesity

Doche, Michael E.; Bochukova, Elena G.; Su, Hsiao Wen; Pearce, Laura R.; Keogh, Julia M.; Henning, Elana; Cline, Joel M.; Dale, Anne; Cheetham, Tim; Barroso, Inês; Argetsinger, Lawrence S.; O’Rahilly, Stephen; Rui, Liangyou; Carter‐Su, Christin; Farooqi, I. Sadaf

doi:10.1172/jci62696

Cited by 165 publications

(111 citation statements)

References 23 publications

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“…SH2B1 mutations were detected among 800 obese children and adolescents with insulin resistance (Pro90His, Thr175Asn, Pro322Ser, Phe344Leufs*20, Thr564Ala, Ala663Val, Ala723Val) [25,26]. All variants impaired GH-induced cell motility when present in the alpha isoform of SH2B1.…”

Section: Introductionmentioning

confidence: 99%

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

Giuranna¹,

Volckmar²,

Heinen³

et al. 2018

Obes Facts

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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.

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Section: Introductionmentioning

confidence: 99%

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

Giuranna¹,

Volckmar²,

Heinen³

et al. 2018

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“…Sh2b1-null mice are also insulin resistant and exhibit impaired insulin signalling (Morris et al 2009). We have found that deletion of a 220-kb segment of 16p11.2, which includes SH2B1 (Bochukova et al 2010) and mutations in the gene itself (Doche et al 2012), is associated with highly penetrant familial severe earlyonset obesity which may in part be due to altered leptin signalling. However, SH2B1 modulates signalling by a variety of ligands that bind to receptor tyrosine kinases or JAK-associated cytokine receptors, including insulin, growth hormone (GH) and nerve growth factor (Chua 2010); as such mutations in the SH2B1 gene have been associated with additional phenotypes including severe insulin resistance and behavioural abnormalities in some patients (Doche et al 2012).…”

Section: Mutations In Molecules Involved In Leptin Signallingmentioning

confidence: 98%

20 YEARS OF LEPTIN: Human disorders of leptin action

Farooqi¹,

O’Rahilly²

2014

Journal of Endocrinology

242

156

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The discovery of leptin has provided a robust framework upon which our current understanding of the mechanisms involved in energy homeostasis has been built. In this review, we describe how the identification of humans with mutations in the genes encoding leptin and the leptin receptor and the characterisation of the associated clinical phenotypes have provided insights into the role of leptin-responsive pathways in the regulation of eating behaviour, intermediary metabolism and the onset of puberty. Importantly, administration of recombinant human leptin in leptin deficiency represents the first mechanistically based targeted therapy for obesity and has provided immense clinical benefits for the patients concerned. In subsequent years, we and others have shown that human obesity can result from a multiplicity of defects in the pathways downstream of leptin signalling within the brain.

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“…However, Thr484Ala substitution alone is not sufficient to cause obesity [117] , raising the possibility that other unidentified SH2B1 mutations, which co-segregate with rs7498665, may increase risk for obesity. Several SH2B1 missense mutations (P90H, T175N, P322S and F344LfsX20) were reported to be genetically linked to obesity and insulin resistance in mixed European descents [118] . F344LfsX20A mutation causes a frameshift, resulting in production of a C-terminally-truncated SH2B1 variant lacking the entire SH2 domain [118] .…”

Section: Sh2b1 Regulates Reproduction In Micementioning

confidence: 99%

“…Several SH2B1 missense mutations (P90H, T175N, P322S and F344LfsX20) were reported to be genetically linked to obesity and insulin resistance in mixed European descents [118] . F344LfsX20A mutation causes a frameshift, resulting in production of a C-terminally-truncated SH2B1 variant lacking the entire SH2 domain [118] . A separate study reported that SH2B1 g.9483(C/T) missense mutation, but not Thr175Asp non-synonymous variant (rs147094247), is linked to obesity [119] .…”

Section: Sh2b1 Regulates Reproduction In Micementioning

confidence: 99%

“…SH2B1 rs7498665 is associated with type 2 diabetes in both United Kingdom [92] and French populations [121] . Heterozygous carriers of a P90H, T175N, P322S, or F344LfsX20 non-synonymous variant develop severe early-onset obesity as well as insulin resistance and type 2 diabetes [118] . We reported that peripheral SH2B1 regulates insulin sensitivity and glucose metabolism independently of its action on body weight in mice [48] .…”

Section: Sh2b1 Mutations Increase Risk For Type 2 Diabetes In Humansmentioning

confidence: 99%

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SH2B1 regulation of energy balance, body weight, and glucose metabolism

Rui

2014

WJD

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The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo-or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IRS2. SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/ IRS1/2 signaling complex. SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins. Accordingly, genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, and type 2 diabetes in mice. Neuronspecific overexpression of SH2B1β transgenes protects against diet-induced obesity and insulin resistance. SH2B1 in pancreatic β cells promotes β cell expansion and insulin secretion to counteract insulin resistance in obesity. Moreover, numerous SH2B1 mutations are genetically linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Unlike SH2B1, SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis. The metabolic function of the SH2B family is conserved from insects to humans. Key words: Obesity; Type 2 diabetes; Leptin resistance; Insulin resistance; Glucose intolerance; Hypothalamus; Energy balance; Food intake; Hyperphagia; Nonalcoholic fatty liver disease Core tip: The Src homology 2B (SH2B) family members mediate cell signaling in response to a variety of hormones, cytokines, and growth factors. In the brain, SH2B1 enhances leptin signaling and leptin's antiobesity action. In peripheral tissues, SH2B1 cell-autonomously enhances insulin signaling. In pancreatic islets, SH2B1 is required for compensatory β cell expansion in response to insulin resistance and β cell stress. SH2B1-deficiency results in severe leptin resistance, energy imbalance, obesity, and type 2 diabetes. SH2B1 mutations are linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Thus, SH2B1 is a critical metabolic regulator in mammals.Rui L. SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes 2014; 5(4): 511-526 Available from:

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Human SH2B1 mutations are associated with maladaptive behaviors and obesity

Cited by 165 publications

References 23 publications

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

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

20 YEARS OF LEPTIN: Human disorders of leptin action

SH2B1 regulation of energy balance, body weight, and glucose metabolism

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