Endocrine Abstracts

Obesity, a multifactorial chronic endocrine-metabolic disease, represents one of the most serious and complex global health threats, as it is commonly associated with multiple and severe comorbidities (e.g. diabetes type-2). Indeed, as a source of severe metabolic-dysregulation, obesity alters physiological, homeostatic gene expression patters in multiple metabolic-tissues, including the central metabolic hub, i.e. the liver. However, the precise molecular mechanisms underlying this pathological association are still unknown. There is emerging evidence that alternative mRNA splicing, the key mechanism providing transcript/protein-diversity from a single gene, is dysregulated in many tissues under adverse metabolic-conditions, such as obesity, and can influence the development and progression of several pathologies. Here, we hypothesized that an alteration in the splicing machinery could occur in key metabolic tissues, such as the liver, during obesity, which might ultimately be associated with the progression of hepatic disease. To ascertain this question, an array of selected components of the major- (n=13) and minor-spliceosome (n=4), and associated splicing-factors (n=28) was developed, and their expression levels were evaluated using a Fluidigm methodology, in the liver of obese mice (fed a high-fat diet) compared with control-lean mice (fed a low-fat diet). Additionally, we analysed whether the splicing processes are regulated by metformin (an agent used to treat type-2-diabetes) in livers of obese vs. control-lean mice. Results revealed that expression of some splicing-machinery factors was altered in the liver of obese vs. control-lean mice (e.g. up-regulation: RNU1, RNU2, RBM22, SRSF3; down-regulation: RNU11). Interestingly, we found that metformin similarly altered the hepatic expression of two splicing-machinery factors (i.e. up-regulation of SRSF10 and PSF) in obese- and lean-mice. However, many other components of the splicing machinery-associated factors (i.e. RNU1, U2AF1, PRPF40A, PRPF8, RBM22, RNU6atac, CELF1, SRSF5, SRSF6, SRSF9, SNW1, SND1, SFPQ, KHDRBS1) were exclusively up-regulated by metformin under normal-lean, but not obese, conditions which might suggest that the liver of obese-mice (which had fatty-liver and were hyperglycemic and hyperinsulinemic) might be partially resistant to alterations in the splicing machinery in response to metformin. Altogether, our results suggest that the alteration of the some components of the cellular splicing machinery in hepatocytes could be responsible for the dysregulated expression of multiple splice variants produced in the liver under obesity conditions. Ongoing studies would clarify the potential physiological implications of these findings, which may provide novel diagnostic biomarkers and therapeutic tools to treat hepatic-diseases.