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J Clin Invest. 2012 Dec;122(12):4732-6. doi: 10.1172/JCI62696. Epub 2012 Nov 19.

Human SH2B1 mutations are associated with maladaptive behaviors and obesity.

Author information

1
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5622, USA.

Erratum in

  • J Clin Invest. 2013 Jan 2;123(1):526. Saeed, Sadia [added].

Abstract

Src homology 2 B adapter protein 1 (SH2B1) modulates signaling by a variety of ligands that bind to receptor tyrosine kinases or JAK-associated cytokine receptors, including leptin, insulin, growth hormone (GH), and nerve growth factor (NGF). Targeted deletion of Sh2b1 in mice results in increased food intake, obesity, and insulin resistance, with an intermediate phenotype seen in heterozygous null mice on a high-fat diet. We identified SH2B1 loss-of-function mutations in a large cohort of patients with severe early-onset obesity. Mutation carriers exhibited hyperphagia, childhood-onset obesity, disproportionate insulin resistance, and reduced final height as adults. Unexpectedly, mutation carriers exhibited a spectrum of behavioral abnormalities that were not reported in controls, including social isolation and aggression. We conclude that SH2B1 plays a critical role in the control of human food intake and body weight and is implicated in maladaptive human behavior.

PMID:
23160192
PMCID:
PMC3533535
DOI:
10.1172/JCI62696
[Indexed for MEDLINE]
Free PMC Article

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