Investigating the Pleiotropic Roles of COBLL1 in the Development of Type 2 Diabetes and Endometriosis

Type 2 diabetes (T2D) is a highly prevalent and complex metabolic disorder with increasing global incidence. Genome-wide association studies (GWAS) have identified multiple loci linked to T2D, yet the mechanisms underlying these associations remain largely undefined. Among these, the 2q24.3 locus is a pleiotropic risk factor implicated in body fat distribution, lipid levels, and other metabolic traits. Notably, variants at the 2q24.3 locus, specifically the intronic variant rs6712203 within the COBLL1/GRB14 locus, have been shown to regulate COBLL1 expression in human adipocytes and are associated with metabolic disorders, inflammation, endometriosis, and prostate cancer. This doctoral research, as part of broader efforts detailed in Glunk et al. (2023), focused on elucidating the functional role of COBLL1 in metabolic regulation. Through targeted gene silencing in human primary adipose-derived mesenchymal stem cells undergoing in vitro differentiation, it was demonstrated that COBLL1 influences adipocyte differentiation via actin cytoskeleton alterations. Additionally, COBLL1 knockdown resulted in decreased adiponectin expression, suggesting a role in inflammatory modulation. Conversely, COBLL1 silencing in T-HESC, a uterine cell line, and human endometrial stromal cells indicated an increase in decidualization markers, contrasting with findings in adipocytes. This differential response highlights the gene's tissue-specific roles and its potential involvement in endometriosis, as indicated by upregulated inflammatory markers in T-HESC post-knockdown. This thesis provides fundamental insights into COBLL1's varied biological functions and lays the groundwork for further investigations into its role in metabolic and reproductive disorders. Further research is needed to decipher the molecular drivers of diseases like endometriosis, leveraging findings from this comprehensive study.