PPARGin Human Adipogenesis: Differential Contribution of Canonical Transcripts and Dominant Negative Isoforms

摘要

The nuclear receptor PPARγis a key regulator of adipogenesis, and alterations of its function are associated with different pathological processes related to metabolic syndrome. We recently identified twoPPARGtranscripts encoding dominant negative PPARγisoforms. The existence of differentPPARGvariants suggests that alternative splicing is crucial to modulate PPARγfunction, underlying some underestimated aspects of its regulation. Here we investigatePPARGexpression in different tissues and cells affected in metabolic syndrome and, in particular, during adipocyte differentiation of human mesenchymal stem cells. We defined the transcript-specific expression pattern ofPPARGvariants encoding both canonical and dominant negative isoforms and identified a novelPPARGtranscript,γ1ORF4. Our analysis indicated that, during adipogenesis, the transcription of alternativePPARGvariants is regulated in a time-specific manner through differential usage of distinct promoters. In addition, our analysis describes—for the first time—the differential contribution of three ORF4 variants to this process, suggesting a still unexplored role for these dominant negative isoforms during adipogenesis. Therefore, our results highlight crucial aspects ofPPARGregulation, suggesting the need of further investigation to rule out the differential impact of allPPARGtranscripts in both physiologic and pathologic conditions, such as metabolism-related disorders.