Nck2 Regulates Adiposity and Adiposity-Related Metabolic Disorders in Mice and Human

Obesity is linked to the development of metabolic disorders. Expansion of white adipose tissue (WAT) from hypertrophy of pre-existing adipocytes and/or differentiation of precursors into new mature adipocytes contributes to obesity. We found that Nck2 expression is largely restricted to WAT, raising the hypothesis that it may play a unique function in that tissue. Using mice lacking Nck2, we found that Nck2 regulates adipocyte hypertrophy thus contributing to increased adiposity and progressive glucose intolerance, insulin resistance and hepatic steatosis. These findings were recapitulated in humans such that Nck2 expression in omental WAT was inversely correlated with the degree of obesity. Mechanistically, Nck2 deficiency promoted the induction of an adipocyte differentiation program and signaling by the PERK-eIF2alpha-ATF4 pathway in agreement with a role for the unfolded protein response in adipogenesis. These findings uncover Nck2 as a novel regulator of adipogenesis and that perturbation in its functionality contributes to adiposity-related metabolic disorders. Differential gene expression profile between epididymal white adipose tissue of Nck2-/- and Nck2+/+ mice by RNA sequencing (Illumina HiSEq 2000)肥胖与代谢紊乱的发生发展密切相关。白色脂肪组织（white adipose tissue，简称WAT）的扩张——由已有脂肪细胞肥大增生和/或前体细胞分化为成熟新生脂肪细胞所驱动——是肥胖发生的重要诱因。我们的研究发现，Nck2的表达主要局限于白色脂肪组织，由此提出假说：Nck2在该组织中可能发挥独特的调控功能。利用Nck2基因敲除小鼠开展实验，我们发现Nck2可调控脂肪细胞肥大，进而加剧肥胖进展，并引发进行性葡萄糖耐受不良、胰岛素抵抗及肝脂肪变性。该研究结果在人类样本中得到验证：网膜白色脂肪组织中的Nck2表达水平与肥胖程度呈负相关。从分子机制来看，Nck2缺失可促进脂肪细胞分化程序的激活，并调控PERK-eIF2alpha-ATF4通路的信号转导，这与未折叠蛋白反应（unfolded protein response）在脂肪生成中的作用相符。本研究揭示Nck2是脂肪生成的新型调控因子，其功能异常可诱发肥胖相关代谢紊乱。本数据集通过RNA测序（Illumina HiSEq 2000），获取了Nck2敲除（Nck2-/-）与野生型（Nck2+/+）小鼠附睾白色脂肪组织的差异基因表达谱。