Perfluorooctanesulfonate Induces an Atypical Adipocyte Phenotype: Promoting Adipogenesis and Thermogenesis via PPARγ Signaling and m6A RNA Modifications in 3T3-L1 Cells

High Resolution Image Download MS PowerPoint Slide This study examined the effects of PFOS on adipocyte differentiation and lipid metabolism in mouse 3T3-L1 preadipocytes. At 10 and 100 μM, PFOS enhanced adipogenesis, promoting intracellular oil droplet accumulation and upregulating key markers, including PPARγ, perilipin, fatty acid-binding protein 4 (FABP4), lipoprotein lipase (LPL), CD36, fatty acid synthase (FASN), and glucose transporter 4 (GLUT4). It also increased adipokines (adiponectin and resistin). Compared to troglitazone (TGZ), a PPARγ agonist, PFOS induced milder differentiation effects. Cotreatment with PFOS and TGZ diminished TGZ’s pro-adipogenic potency, indicating potential interference. PFOS further influenced N6-methyladenosine (m6A) RNA modifications by altering the expression of m6A writers (METTL3 and VIR) and eraser (FTO), suggesting post-transcriptional regulation of adipogenic genes. Functional evaluations showed that PFOS preserved forskolin-stimulated lipolysis without impairing it. However, it upregulated metabolic markers, including carnitine palmitoyltransferase-1a (CPT1a), pyruvate dehydrogenase kinase (PDHK), and fibroblast growth factor-21 (FGF21), alongside elevated ATP levels in the 100 μM PFOS-treated group. These molecular changes suggest enhanced energy expenditure or energy stress, despite the cells’ morphological resemblance to white adipocytes. This duality likely arises from PFOS’s modulation of PPARγ signaling and m6A RNA modifications. By elucidating these mechanisms, the study highlights potential metabolic risks associated with PFOS exposure.