Deletion Of The Brain-Specific Alpha And Delta Isoforms Of Adapter Protein Sh2b1 Protects Mice From Obesity

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, SH2B1 beta and SH2B1 gamma exhibit ubiquitous expression, whereas SH2B1 alpha and SH2B1 delta are essentially restricted to the brain. To understand the roles for SH2B1 alpha and SH2B1 delta in energy balance and glucose metabolism, we generated mice lacking these brain-specific isoforms (alpha delta knockout [alpha delta KO] mice). alpha delta KO 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, alpha delta KO mice exhibit leptin sensitivity that is similar to that of wild-type mice by multiple measures. Thus, decreasing the abundance of SH2B1 alpha and/or SH2B1 delta 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.