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

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 <i>per</i> 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 (<i>Hmgcs2</i>) was shared between PFOA and HFPO-DA groups from 2 to 8 days. <i>Hmgcs2</i> could regulate adipocyte browning induced by PFOA and HFPO-DA, and this observation was lost when <i>Hmgcs2</i> was knocked down. Our study suggests that PFOA and HFPO-DA could play dual roles in the differentiation of 3T3-L1 adipocytes, and <i>Hmgcs2</i> might be a target of PFOA- and HFPO-DA-induced adipocyte browning.