Transcriptomic landscape of sex differences in obesity and type 2 diabetes in subcutaneous adipose tissue

Obesity represents a significant risk factor in the development of type 2 diabetes (T2D), a chronic metabolic disorder characterized by elevated blood glucose levels. Significant sex differences have been identified in the prevalence, development, and pathophysiology of obesity and T2D; however, the underlying molecular mechanisms remain unclear. This study aims to identify sex-specific biomarkers in obesity and T2D and enhance our understanding of the underlying mechanisms associated with sex differences by integrating expression data.

A systematic review, individual transcriptomic analysis, gene-level meta-analysis, and functional characterization were performed to achieve this aim. Eight studies and 236 subcutaneous adipose tissue samples were analyzed, identifying common and sex-specific biomarkers, many of which were previously associated with obesity or T2D.

The obesity meta-analysis yielded nineteen differentially-expressed biomarkers from a sex-specific perspective (e.g., SPATA18, KREMEN1, NPY4R , and PRM3 ), while a comparison of the expression profiles between sexes in T2D prompted the identification and validation of specific transcriptomic signatures in males ( SAMD9, NBPF3, LDHD , and EHD3 ) and females ( RETN, HEY1, PLPP2 , and PM20D2 ). At the functional level, we highlighted the fundamental role of the Wnt pathway in the development of obesity and T2D in females and the roles of more significant mitochondrial damage and free fatty acids in males.

Overall, our sex-specific meta-analyses supported the detection of differentially expressed genes in males and females associated with the development of obesity and T2D, emphasizing the relevance of sex-based information in biomedical data and opening new avenues for research.

Highlights

• First meta-analysis on WAT with sex as a central perspective in obesity and T2D

• This study identifies 19 sex-differential biomarkers in obesity, highlighting NPY4

• Sex specific transcriptional signatures in SAT in the development of T2D

• Wnt pathway genes show sex-specific roles in obesity and T2D, notably in females

• Obesity increases mitogenesis in male, mediated by SPATA18, with an increased role of free fatty acids in T2D