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The nuclear receptor PPAR  γ   is a key regulator of adipogenesis, and alterations of its function are associated with different pathological processes related to metabolic syndrome. We recently identified two  PPARG  transcripts encoding dominant negative PPAR  γ   isoforms. The existence of different  PPARG  variants suggests that alternative splicing is crucial to modulate PPAR  γ   function, underlying some underestimated aspects of its regulation. Here we investigate  PPARG  expression 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 of  PPARG  variants encoding both canonical and dominant negative isoforms and identified a novel  PPARG  transcript,   γ  1ORF4. Our analysis indicated that, during adipogenesis, the transcription of alternative  PPARG  variants 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 of  PPARG  regulation, suggesting the need of further investigation to rule out the differential impact of all  PPARG  transcripts in both physiologic and pathologic conditions, such as metabolism-related disorders.

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