Time-Course Strategy\nReveals a Dual Potential of Perfluorooctanoic\nAcid and Its Alternative in Adipocyte Differentiation

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