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

• Published in: Diabetes (New York, N.Y.) Vol. 68; no. 11; pp. 2049 - 2062
• Main 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, Hu, Yixin, Stuckey, Jeanne, Farooqi, I Sadaf, Myers, Jr, Martin G, Carter-Su, Christin
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-11-2019
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adipose tissue; Adiposity - genetics; Adolescent; Amino acids; Animals; Child; Child, Preschool; Energy balance; Energy Metabolism - genetics; Female; Glucose; Glucose Intolerance - genetics; Glucose Intolerance - metabolism; Glucose tolerance; Homeostasis; Homeostasis - genetics; Homology; Humans; Insulin; Insulin resistance; Insulin Resistance - genetics; Intolerance; Lethality; Male; Mice; Mice, Transgenic; Obesity; Obesity Studies; Pediatric Obesity - genetics; Pediatric Obesity - metabolism; Phenotypes; Pleckstrin; Pleckstrin Homology Domains - genetics
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db19-0608

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
variants in severely obese children. Four obesity-associated human
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.