Burks, D. J. | bioRxiv Science

bioRxiv2024

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. HighlightsO_LIFirst meta-analysis on WAT with sex as a central perspective in obesity and T2D C_LIO_LIThis study identifies 19 sex-differential biomarkers in obesity, highlighting NPY4 C_LIO_LISex specific transcriptional signatures in SAT in the development of T2D C_LIO_LIWnt pathway genes show sex-specific roles in obesity and T2D, notably in females C_LIO_LIObesity increases mitogenesis in male, mediated by SPATA18, with an increased role of free fatty acids in T2D C_LI

molecular biology↗

bioRxiv2021

Sex bias evaluation of classic and novel Housekeeping Genes in adipose tissue through the massive analysis of transcriptomics data

BackgroundAs the housekeeping genes (HKG) generally involved in maintaining essential cell functions are typically assumed to exhibit constant expression levels across cell types, they are commonly employed as internal controls in gene expression studies. Nevertheless, HKG may vary gene expression profile according to different variables introducing systematic errors into experimental results. Sex bias can indeed affect expression display, however, up to date, sex has not been typically considered as a biological variable. MethodsIn this study, we evaluate the expression profiles of six classical housekeeping genes (four metabolic: GAPDH, HPRT, PPIA, and UBC, and two ribosomal: 18S and RPL19) to determine expression stability in adipose tissues (AT) of Homo sapiens and Mus musculus and check sex bias and their overall suitability as internal controls. We also assess the expression stability of all genes included in distinct whole-transcriptome microarrays available from the Gene Expression Omnibus database to identify sex-unbiased housekeeping genes (suHKG) suitable for use as internal controls. We perform a novel computational strategy based on meta-analysis techniques to identify any sexual dimorphisms in mRNA expression stability in AT and to properly validate potential candidates. ResultsJust above half of the considered studies informed properly about the sex of the human samples, however, not enough female mouse samples were found to be included in this analysis. We found differences in the HKG expression stability in humans between female and male samples, with females presenting greater instability. We propose a suHKG signature including experimentally validated classical HKG like PPIA and RPL19 and novel potential markers for human AT and discarding others like the extensively used 18S gene due to a sex-based variability display in adipose tissue. Orthologs have also been assayed and proposed for mouse WAT suHKG signature. All results generated during this study are readily available by accessing an open web resource (https://bioinfo.cipf.es/metafun-HKG) for consultation and reuse in further studies. ConclusionsThis sex-based research proves that certain classical housekeeping genes fail to function adequately as controls when analyzing human adipose tissue considering sex as a variable. We confirm RPL19 and PPIA suitability as sex-unbiased human and mouse housekeeping genes derived from sex-specific expression profiles, and propose new ones such as RPS8 and UBB. HighlightsO_LIA computational strategy based on massive data analysis revealed that an accurate experimental design for adipose tissue requires the adequate selection of a sex-unbiased housekeeping genes (HKG). C_LIO_LIThe extensively used 18S gene displays sex-based variability in adipose tissue, although PPIA and RPL19 do not, and hence, represent robust HKG. C_LIO_LINew sex-unbiased human and mouse candidate HKG: RPS8 and UBB. C_LIO_LImetafun-HKG (https://bioinfo.cipf.es/metafun-HKG): a freely available web tool to allow users to review stable expression levels of candidate HKG along the large volume of FAIR data. C_LI

genomics↗