Format

Send to

Choose Destination
Diabetes. 2019 Nov;68(11):2049-2062. doi: 10.2337/db19-0608. Epub 2019 Aug 22.

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

Author information

1
Cell and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI.
2
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI.
3
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
4
MRC Epidemiology Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
5
Life Sciences Institute and Departments of Biological Chemistry and Biophysics, University of Michigan, Ann Arbor, MI.
6
Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
7
Cell and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI cartersu@umich.edu.

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.

PMID:
31439647
PMCID:
PMC6804625
[Available on 2020-11-01]
DOI:
10.2337/db19-0608

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center