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- Title
Crucial Role of the SH2B1 PH Domain for the Control of Energy Balance.
- Authors
Flores, Anabel; Argetsinger, Lawrence S.; Stadler, Lukas K. J.; Malaga, Alvaro E.; Vander, Paul B.; DeSantis, Lauren C.; Joe, Ray M.; Cline, Joel M.; Keogh, Julia M.; Henning, Elana; Barroso, Ines; Mendes de Oliveira, Edson; Chandrashekar, Gowri; Clutter, Erik S.; Yixin Hu; Stuckey, Jeanne; Farooqi, I. Sadaf; Myers Jr., Martin G.; Carter-Su, Christin; Hu, Yixin
- Abstract
Disruption of the adaptor protein SH2B1 (SH2-B, PSM) is associated with severe obesity, insulin resistance, and neurobehavioral abnormalities in mice and humans. Here, we identify 15 SH2B1 variants in severely obese children. Four obesity-associated human SH2B1 variants 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/P322S mice exhibited substantial prenatal lethality. Examination of the P322S/+ metabolic phenotype revealed late-onset glucose intolerance. To circumvent P322S/P322S lethality, mice containing a two-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 how SH2B1 controls energy balance and glucose homeostasis.
- Subjects
GLUCOSE intolerance; INSULIN resistance; ADAPTOR proteins; HUMAN abnormalities; OBESITY
- Publication
Diabetes, 2019, Vol 68, Issue 11, p2049
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db19-0608