Crucial Role of the SH2B1 PH Domain for the Control of Energy Balance

Disruption of the adaptor protein SH2B1 is associated with severe obesity, insulin resistance and neurobehavioral abnormalities in mice and humans. Here we identify 15 SH2B1 mutations in severely obese children. Four obesity-associated human SH2B1 mutations lie in the Pleckstrin Homology (PH) domain, suggesting that the PH domain is essential for SH2B1’s function. We generated a mouse model of a human variant in this domain (P322S). P322S/P332S mice exhibited substantial prenatal lethality. Examination of the P322S/+ metabolic phenotype revealed late-onset glucose intolerance. To circumvent P322S/P322S lethality, mice containing a 2-amino acid deletion within the SH2B1 PH domain (ΔP317, R318; ΔPR) were studied. Mice homozygous for ΔPR were born at the expected Mendelian ratio and exhibited obesity plus insulin resistance and glucose intolerance beyond that attributable to their increased adiposity. These studies demonstrate that the PH domain plays a crucial role in SH2B1 control of energy balance and glucose homeostasis.