Human SH2B1 Mutations Are Associated with Maladaptive Behaviors and Obesity

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2012 Nov 20

PMID 23160192

Citations 77

Authors

Michael E Doche

Elena G Bochukova

Hsiao-Wen Su

Laura R Pearce

Julia M Keogh

Elana Henning

Joel M Cline

Sadia Saeed

Anne Dale

Tim Cheetham

Ines Barroso

Lawrence S Argetsinger

Stephen ORahilly

Liangyou Rui

Christin Carter-Su

I Sadaf Farooqi

Affiliations

Soon will be listed here.

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.

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