ABSTRACT
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. CABLES1 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 CABLES1 gene expression in SAT might be altered in obesity and T2D as a consequence of metabolic dysregulation rather than being a causal factor.
Acknowledgments
We gratefully acknowledge the valuable technical, administrative and analytical contributions of co-workers at Uppsala University Hospital and Uppsala University. We would also like to thank Stanko Skrtic, Astra Zeneca for collaboration in early parts of this research, and Argyri Mathioudaki for bioinformatics analysis. We also warmly thank all the participants in the study.
Disclosure statement
PGK is currently employed by AstraZeneca R&D. SH, MV, MHL., MJP and JWE declare no competing interests.
Author contributions
PGK, MV, SH and MJP contributed to study design, acquisition, analysis and interpretation of data; SH wrote the manuscript; MHL contributed to data acquisition; JWE contributed to study design and data interpretation. All co-authors revised the manuscript critically and approved a final version
Data availability statement
Some or all datasets generated during and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/21623945.2023.2242997