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

Area of Science:

• Molecular Endocrinology
• Metabolic Syndrome Research
• Cellular Differentiation

Background:

• The nuclear receptor PPARγ is a critical regulator of adipogenesis.
• Dysregulation of PPARγ is linked to metabolic syndrome pathologies.
• Previously identified PPARG transcripts encode dominant-negative PPARγ isoforms, suggesting alternative splicing's importance in PPARγ regulation.

Purpose of the Study:

• To investigate PPARG expression patterns in tissues affected by metabolic syndrome, specifically during human mesenchymal stem cell adipocyte differentiation.
• To define the transcript-specific expression of PPARG variants, including canonical and dominant-negative isoforms.
• To identify and characterize novel PPARG transcripts and their regulatory mechanisms.

Main Methods:

• Analysis of PPARG expression in various tissues and cells relevant to metabolic syndrome.
• Detailed examination of PPARG transcript-specific patterns during adipocyte differentiation of human mesenchymal stem cells.
• Identification of novel PPARG transcripts, including the γ 1ORF4 variant.

Main Results:

• Defined the transcript-specific expression profile of PPARG variants, encompassing both canonical and dominant-negative isoforms.
• Identified a novel PPARG transcript, designated γ 1ORF4.
• Demonstrated that alternative PPARG variant transcription during adipogenesis is regulated in a time-specific manner via differential promoter usage, with three ORF4 variants contributing distinctly.

Conclusions:

• Alternative splicing of PPARG plays a crucial role in modulating PPARγ function during adipogenesis.
• The novel ORF4 variants exhibit a differential contribution to adipogenesis, suggesting an unexplored role for these dominant-negative isoforms.
• Further investigation into the differential impact of all PPARG transcripts is warranted for understanding both physiological processes and metabolic disorders.