Deletion of the brain-specific α and δ isoforms of adapter protein SH2B1 protects mice from obesity
figureposted on 19.11.2020, 16:10 by Ada Admin, 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, Jr, Christin Carter-Su
Figures are generally photos, graphs and static images that would be represented in traditional pdf publications.
Mice lacking SH2B1 and humans with inactivating mutations 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, SH2B1b and SH2B1g exhibit ubiquitous expression, whereas SH2B1a and SH2B1d are essentially restricted to the brain. To understand the roles for SH2B1a and SH2B1d in energy balance and glucose metabolism, we generated mice lacking these brain-specific isoforms (adKO mice). adKO 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, adKO mice exhibit leptin sensitivity that is similar to that of wild-type mice by multiple measures. Thus, decreasing the abundance of SH2B1a and/or SH2B1d relative to the other SH2B1 isoforms likely shifts energy balance towards 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.