Role of the Beta and Gamma Isoforms of the Adapter Protein SH2B1 in Regulating Energy Balance

Human variants of the adapter protein SH2B1 are associated with severe childhood obesity, hyperphagia, and insulin resistance-phenotypes mimicked by mice lacking Sh2b1. SH2B1 beta and gamma isoforms are expressed ubiquitously, whereas SH2B1 alpha and delta isoforms are expressed primarily in the brain. Restoring SH2B1 beta driven by the neuron-specific enolase promoter largely reverses the metabolic phenotype of Sh2b1-null mice, suggesting crucial roles for neuronal SH2B1 beta in energy balance control. Here we test this hypothesis by using CRISPR/Cas9 gene editing to delete the beta and gamma isoforms from the neurons of mice (SH2B1 beta gamma neuron-specific knockout [NKO] mice) or throughout the body (SH2B1 beta gamma knockout [KO] mice). While parameters of energy balance were normal in both male and female SH2B1 beta gamma NKO mice, food intake, body weight, and adiposity were increased in male (but not female) SH2B1 beta gamma KO mice. Analysis of long-read single-cell RNA seq data from wild-type mouse brain revealed that neurons express almost exclusively the alpha and delta isoforms, whereas neuroglial cells express almost exclusively the beta and gamma isoforms. Our work suggests that neuronal SH2B1 beta and gamma are not primary regulators of energy balance. Rather, non-neuronal SH2B1 beta and gamma in combination with neuronal SH2B1 alpha and delta suffice for body weight maintenance. While SH2B1 beta/gamma and SH2B1 alpha/delta share some functionality, SH2B1 beta/gamma appears to play a larger role in promoting leanness.