<i>CABLES1</i> expression is reduced in human subcutaneous adipose tissue in obesity and type 2 diabetes but may not directly impact adipocyte glucose and lipid metabolism

Cdk5 and Abl enzyme substrate 1 (CABLES1) is a cell cycle regulator that has previously been identified as a candidate gene for obesity-related phenotypes, but little is known about its role in adipose tissue metabolism. In this study, we explore the role of CABLES1 in obesity and type 2 diabetes (T2D) in human subcutaneous adipose tissue (SAT). We performed gene expression analysis of SAT obtained from subjects with and without T2D, and from a second validation cohort consisting of subjects without T2D. We used CRISPR/Cas9 genome editing to perform CABLES1 loss-of-function studies in human primary preadipocytes and assessed them functionally after differentiation. <i>CABLES1</i> gene expression in SAT was decreased in T2D by almost 25%, and inversely associated with insulin resistance markers and hyperglycaemia. mRNA levels were reduced with increasing BMI and negatively correlated with obesity markers. We found that adipocytes are likely the main CABLES1-expressing cell type in SAT, but CABLES1 depletion in adipocytes caused no phenotypical changes in regards to differentiation, glucose uptake, or expression of key genes of adipocyte function. These findings suggest that <i>CABLES1</i> gene expression in SAT might be altered in obesity and T2D as a consequence of metabolic dysregulation rather than being a causal factor.Cdk5与Abl酶底物1（CABLES1）是一种细胞周期调控因子，此前被鉴定为肥胖相关表型的候选基因，但目前对其在脂肪组织代谢中的作用尚不清楚。本研究针对人类皮下脂肪组织（subcutaneous adipose tissue，缩写SAT），探讨了CABLES1在肥胖及2型糖尿病（type 2 diabetes，缩写T2D）中的作用。我们对来自伴T2D、不伴T2D受试者，以及另一组无T2D的验证队列受试者的SAT组织开展了基因表达分析。我们利用CRISPR/Cas9基因组编辑技术，在人类原代前体脂肪细胞中进行CABLES1功能丧失研究，并在细胞诱导分化完成后对其进行功能评估。在T2D患者的SAT组织中，CABLES1基因表达水平下调近25%，且与胰岛素抵抗标志物及高血糖症呈负相关。其mRNA水平随体重指数（Body Mass Index，缩写BMI）升高而降低，并与肥胖相关标志物呈负相关。我们发现，脂肪细胞或许是SAT组织中表达CABLES1的主要细胞类型，但脂肪细胞中CABLES1的缺失并未在细胞分化、葡萄糖摄取以及脂肪细胞功能关键基因的表达方面引发明显表型改变。上述研究结果表明，SAT组织中CABLES1基因表达的改变可能是肥胖与T2D引发代谢失调的结果，而非致病因素。