Regulation of UCP1 expression by PPARα and pemafibrate in human beige adipocytes

Aims: Thermogenic adipocytes are able to dissipate energy as heat from lipids and carbohydrates through enhanced uncoupled respiration, due to UCP1 activity. PPAR family of transcription factors plays an important role in adipocyte biology. The purpose of this work was to characterize the role of PPARα and pemafibrate in the control of thermogenic adipocyte formation and function.

Materials and methods: We used human multipotent adipose-derived stem cells and primary cultures of stroma-vascular fraction cells, transfected with siRNA against PPARα, differentiated into white or beige adipocytes, by the treatment of rosiglitazone or pemafibrate. The expression of key marker genes of adipogenesis and thermogenesis was determined using RT-qPCR and Western blotting. An RNAseq analysis was also performed.

Key findings: We show that inhibition of PPARα mRNA increases UCP1 mRNA and protein expression in beige adipocytes induced by rosiglitazone. Knock-down of PPARα also increases stimulated glycerol release. Pemafibrate, described as a selective PPARα modulator, induces adipogenesis and the expression of UCP1 in the absence of PPARα expression. These effects are inhibited by a specific PPARγ antagonist highly suggesting that the pemafibrate effects in adipogenesis and beiging were mediated by PPARγ.

Significance: Conversion of white into thermogenic adipocytes is mainly due to the activation of PPARγ. Moreover, we show that PPARα seems to act as a hindrance for PPARγ-dependent beiging. Our data question the role of PPARα in human adipocyte browning and the specificity of pemafibrate in adipocytes.