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

Rui, Liangyou

doi:10.4239/wjd.v5.i4.511

Cited by 70 publications

(65 citation statements)

References 152 publications

(270 reference statements)

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“…As expected, obese SH2B1 KO mice develop hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance and NIDDM [35]. Interestingly, central and peripheral SH2B1 seem to regulate insulin sensitivity and glucose metabolism independently of its action on body weight in man and mice [36].…”

Section: Sh2b1 Deficiencysupporting

confidence: 64%

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

Stagi¹,

Bianconi²,

Sammarco³

et al. 2017

Adiposity - Omics and Molecular Understanding

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Historically, some genetic syndromes and monogenic forms of obesity have been identified by clinical features and by sequencing candidate genes in patients with severe obesity. The phenotypic expression of genetic factors involved in obesity is variable, thereby allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. Many of the findings emerged from studying families who displayed a classical Mendelian pattern of inheritance. On the contrary, patients with syndromic obesity show a various degree of intellectual disability, different dysmorphic features, and organ-specific abnormalities. But to date, not all involved genes have been identified so far. New diagnostic tools, such as genome-wide studies, array CGH, and whole-exome sequencing, have highlighted more complex models of inheritance, and even more candidate genes were identified. This increase of knowledge may provide insights into the mechanisms involved in the regulation of body weight and finally lead to specific treatments. In these patients, hyperphagia is often a primary phenotypic component. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present today with a lack of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments. We have evaluated retrospectively the literature data on weight, body mass index (BMI), clinical features, treatments, and treatment response in pediatric patients with forms of genetic obesity. However, this chapter provides an updated picture of emerging knowledge outlined by the more comprehensive genetic approaches, trying to outline more candidate genes for these forms of genetic obesity. Relevant papers will be identified through systematic searches of the PubMed, EMBASE and Cochrane databases. All published studies in the English language concerning these disorders will be evaluated. Keywords in the

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Section: Sh2b1 Deficiencysupporting

confidence: 64%

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

Stagi¹,

Bianconi²,

Sammarco³

et al. 2017

Adiposity - Omics and Molecular Understanding

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“…SH2B1 also enhances insulin receptor autophosphorylation after insulin stimulation and protects IRS and JAK from dephosphorylation [23,24]. Additionally, JAK and IRS are also downstream effectors of growth hormone (GH), insulin like growth factor 1 (IGF-1), (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), leading to the assumption that the signaling of all these hormones is potentially affected by SH2B1 mutations [19]. …”

Section: Introductionmentioning

confidence: 99%

“…Leptin and insulin signaling are the main pathways involved in SH2B1 action on energy homeostasis [19]. SH2B1 promotes leptin signaling by stimulating Janus kinase (JAK1 and JAK2) activity and the assembly of JAK2 / insulin receptor substrate (IRS1 and IRS2) complexes [20,21,22].…”

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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“…SH2B1 also participates in the downregulation of FTO through STAT3 signaling in the hypothalamus (See Figure 1). Genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia and obesity [158]. Notably, the obesity in Sh2b1-null mice can be reversed by targeted Sh2b1 expression in neurons, suggesting that the effects of this gene in obesity are mediated through the CNS [159].…”

Section: Src-homology 2 Domain-containing Protein B1mentioning

confidence: 98%

Discussing the Putative Role of Obesity-Associated Genes in the Etiopathogenesis of Eating Disorders

Gervasini

Gamero-Villarroel

2015

Pharmacogenomics

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In addition to the identification of mutations clearly related to Mendelian forms of obesity; genome-wide association studies and follow-up studies have in the last years pinpointed several loci associated with BMI. These genetic alterations are located in or near genes expressed in the hypothalamus that are involved in the regulation of eating behavior. Accordingly, it seems plausible that these SNPs, or others located in related genes, could also help develop aberrant conduct patterns that favor the establishment of eating disorders should other susceptibility factors or personality dimensions be present. However, and somewhat surprisingly, with few exceptions such as BDNF, the great majority of the genes governing these pathways remain untested in patients with anorexia nervosa, bulimia nervosa or binge-eating disorder. In the present work, we review the few existing studies, but also indications and biological concepts that point to these genes in the CNS as good candidates for association studies with eating disorder patients.

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

Cited by 70 publications

References 152 publications

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

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

Discussing the Putative Role of Obesity-Associated Genes in the Etiopathogenesis of Eating Disorders

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