PDF(Pubmed)
Abstract：
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.
摘要：
衔接蛋白SH2B1的人类变体与严重的儿童肥胖有关，食欲亢进,和缺乏Sh2b1的小鼠模拟的胰岛素抵抗表型。SH2B1β和γ亚型普遍表达，而SH2B1α和δ同种型主要在脑中表达。恢复由神经元特异性烯醇化酶启动子驱动的SH2B1β在很大程度上逆转了Sh2b1-null小鼠的代谢表型，提示神经元SH2B1β在能量平衡控制中的关键作用。在这里，我们通过使用CRISPR/Cas9基因编辑从小鼠（SH2B1βγ神经元特异性敲除[NKO]小鼠）或整个身体（SH2B1βγ敲除[KO]小鼠）的神经元中删除β和γ亚型来测试这一假设。虽然雄性和雌性SH2B1βγNKO小鼠的能量平衡参数正常，食物摄入量,体重,雄性(而非雌性)SH2B1βγKO小鼠肥胖增加。对来自野生型小鼠大脑的长读单细胞RNA序列数据的分析显示，神经元几乎只表达α和δ亚型，而神经胶质细胞几乎只表达β和γ亚型。我们的工作表明，神经元SH2B1β和γ不是能量平衡的主要调节因子。相反，非神经元SH2B1β和γ与神经元SH2B1α和δ的组合足以维持体重。虽然SH2B1β/γ和SH2B1α/δ共享一些功能，SH2B1β/γ似乎在促进稀薄中起较大作用。
