Deletion of brain-specific isoforms of adapter protein SH2B1 protects mice from obesity in a non-leptin-mediated manner

Deletion or mutation of SH2B1 (SH2-B, PSM) is associated with severe obesity and insulin resistance in mice and humans. SH2B1 is alternatively spliced into four known isoforms: a, b, g, and d. Contrasting the ubiquitous expression of SH2B1b and g, SH2B1a and d are expressed almost exclusively in brain. Here, we generated mice lacking the brain-specific SH2B1 isoforms (SH2B1adKO mice). SH2B1adKO mice are protected from weight gain on standard and high fat diets, a phenotype caused by hypophagia. SH2B1adKO mice exhibit improvements in glucose homeostasis, yet these are mostly adiposity-dependent. Surprisingly, SH2B1adKO mice demonstrate normal leptin sensitivity. RNA sequencing highlights potential mechanisms underlying the decreased appetite of SH2B1adKO mice including gene expression changes associated with neuronal synapses. These findings suggest that SH2B1a and/or d are key regulators of energy balance. Furthermore, they highlight the profound importance of alternative splicing regulation for body weight. Hypothalamus mRNA was sequenced from control (WT, n = 9) and mutant mice lacking alpha/delta isoforms of Sh2b1 (SH2B1adKO, n = 12) to identify genes differentially expressed in mutant animals.SH2B1（SH2-B、PSM）的缺失或突变与小鼠和人类的重度肥胖及胰岛素抵抗密切相关。SH2B1可通过可变剪接产生四种已知异构体：a、b、γ和δ。与SH2B1b和γ的广泛表达形成对比的是，SH2B1a和δ几乎仅在大脑组织中表达。本研究构建了缺失脑特异性SH2B1异构体的小鼠（即SH2B1adKO小鼠）。实验结果显示，SH2B1adKO小鼠在普通饲料与高脂饲料喂养条件下均能抵抗体重增加，该表型由摄食量减少所致。SH2B1adKO小鼠的葡萄糖稳态得到改善，但此类改善大多为脂肪量依赖性的。令人意外的是，SH2B1adKO小鼠的瘦素敏感性保持正常。RNA测序分析揭示了SH2B1adKO小鼠食欲降低的潜在分子机制，其中包括与神经元突触相关的基因表达改变。上述研究结果表明，SH2B1a和/或δ是机体能量平衡的关键调控因子。此外，本研究凸显了可变剪接调控对于体重维持的重要意义。本研究对对照组（野生型，n=9）以及缺失Sh2b1 α/δ异构体的突变小鼠（SH2B1adKO，n=12）的下丘脑mRNA进行了测序，旨在鉴定突变动物体内的差异表达基因。