Deletion of the Brain-Specific α and δ Isoforms of Adapter Protein SH2B1 Protects Mice From Obesity.

Citation
Cote, J. L., et al. “Deletion Of The Brain-Specific Α And Δ Isoforms Of Adapter Protein Sh2B1 Protects Mice From Obesity.”. Diabetes, pp. 400-414.
Center University of Michigan
Author Jessica L Cote, Lawrence S Argetsinger, Anabel Flores, Alan C Rupp, Joel M Cline, Lauren C DeSantis, Alexander H Bedard, Devika P Bagchi, Paul B Vander, Abrielle M Cacciaglia, Erik S Clutter, Gowri Chandrashekar, Ormond A MacDougald, Martin G Myers, Christin Carter-Su
Abstract

Mice lacking SH2B1 and humans with variants of SH2B1 display severe obesity and insulin resistance. SH2B1 is an adapter protein that is recruited to the receptors of multiple hormones and neurotrophic factors. Of the four known alternatively spliced SH2B1 isoforms, SH2B1β and SH2B1γ exhibit ubiquitous expression, whereas SH2B1α and SH2B1δ are essentially restricted to the brain. To understand the roles for SH2B1α and SH2B1δ in energy balance and glucose metabolism, we generated mice lacking these brain-specific isoforms (αδ knockout [αδKO] mice). αδKO mice exhibit decreased food intake, protection from weight gain on standard and high-fat diets, and an adiposity-dependent improvement in glucose homeostasis. SH2B1 has been suggested to impact energy balance via the modulation of leptin action. However, αδKO mice exhibit leptin sensitivity that is similar to that of wild-type mice by multiple measures. Thus, decreasing the abundance of SH2B1α and/or SH2B1δ relative to the other SH2B1 isoforms likely shifts energy balance toward a lean phenotype via a primarily leptin-independent mechanism. Our findings suggest that the different alternatively spliced isoforms of SH2B1 perform different functions in vivo.

Year of Publication
2021
Journal
Diabetes
Volume
70
Issue
2
Number of Pages
400-414
Date Published
02/2021
ISSN Number
1939-327X
DOI
10.2337/db20-0687
Alternate Journal
Diabetes
PMID
33214137
PMCID
PMC7881872