Time-Course Strategy Reveals a Dual Potential of Perfluorooctanoic Acid and Its Alternative in Adipocyte Differentiation

Abstract

Exposure to perfluorooctanoic acid (PFOA) and hexafluoropropylene oxide dimer acid (HFPO–DA) was associated with adipogenesis. However, potential mechanisms remain to be elucidated. Herein, a 3T3-L1 adipocyte model was used to explore the dynamic changes in adipocyte differentiation (2, 4, and 8 days) under PFOA and HFPO–DA exposure. PFOA and HFPO–DA increased the adipocyte formation rate and intracellular levels of triglycerides (TG). Meanwhile, adipocyte browning was induced by PFOA and HFPO–DA, which was characterized by small lipid droplets, low levels of TG per adipocyte, increased ATP levels, and elevated mitochondrial respiration activities with time-dependent differentiation. The browning potency indexes of PFOA and HFPO–DA were approximately 1.5 times higher than those of the controls. Time-course transcriptomics analysis showed that PFOA and HFPO–DA activated the biological process of adipocyte browning but different gene expression patterns regulated adipocyte browning. Only overexpressed hydroxymethylglutaryl-CoA synthase (Hmgcs2) was shared between PFOA and HFPO–DA groups from 2 to 8 days. Hmgcs2 could regulate adipocyte browning induced by PFOA and HFPO–DA, and this observation was lost when Hmgcs2 was knocked down. Our study suggests that PFOA and HFPO–DA could play dual roles in the differentiation of 3T3-L1 adipocytes, and Hmgcs2 might be a target of PFOA- and HFPO–DA-induced adipocyte browning.