Role of the Beta and Gamma Isoforms of the Adapter Protein SH2B1 in Regulating Energy Balance.
Lawrence S ArgetsingerAnabel FloresNadezhda SvezhovaMichael EllisCaitlin ReynoldsJessica L CoteJoel M ClineMartin G MyersChristin Carter-SuPublished in: Endocrinology (2023)
Human variants of the adapter protein SH2B1 are associated with severe childhood obesity, hyperphagia, and insulin resistance-phenotypes mimicked by mice lacking Sh2b1. SH2B1β and γ isoforms are expressed ubiquitously, whereas SH2B1α and δ isoforms are expressed primarily in the brain. Restoring SH2B1β driven by the neuron-specific enolase promoter largely reverses the metabolic phenotype of Sh2b1-null mice, suggesting crucial roles for neuronal SH2B1β in energy balance control. Here we test this hypothesis by using CRISPR/Cas9 gene editing to delete the β and γ isoforms from the neurons of mice (SH2B1βγ neuron-specific knockout [NKO] mice) or throughout the body (SH2B1βγ knockout [KO] mice). While parameters of energy balance were normal in both male and female SH2B1βγ NKO mice, food intake, body weight, and adiposity were increased in male (but not female) SH2B1βγ KO mice. Analysis of long-read single-cell RNA seq data from wild-type mouse brain revealed that neurons express almost exclusively the α and δ isoforms, whereas neuroglial cells express almost exclusively the β and γ isoforms. Our work suggests that neuronal SH2B1β and γ are not primary regulators of energy balance. Rather, non-neuronal SH2B1β and γ in combination with neuronal SH2B1α and δ suffice for body weight maintenance. While SH2B1β/γ and SH2B1α/δ share some functionality, SH2B1β/γ appears to play a larger role in promoting leanness.
Keyphrases
- wild type
- single cell
- rna seq
- body weight
- insulin resistance
- high fat diet induced
- crispr cas
- type diabetes
- spinal cord injury
- signaling pathway
- spinal cord
- physical activity
- brain injury
- genome wide
- deep learning
- weight gain
- weight loss
- cell proliferation
- artificial intelligence
- cerebral ischemia
- high fat diet
- subarachnoid hemorrhage
- binding protein
- amino acid
- data analysis
- protein protein
- pluripotent stem cells
- cell cycle arrest