Metabolic and circadian bioenergetic alterations following perfluorooctanoic acid exposure and high-fat diet in female C57BL/6 mice.

Exposure to per- and polyfluoroalkyl substances (PFAS) elicits changes in various metabolic responses but few studies have evaluated whole-body metabolic changes. This study compared whole-body bioenergetics in adult female C57BL/6 mice orally dosed with 0 or 7.5 mg/kg perfluorooctanoic acid (PFOA) or fed a 60% high fat diet (HFD) for 24 h or 15 d. After 24 h, HFD mice showed increased oxygen consumption (VO2) and reduced active-phase respiratory exchange ratio (RER), indicating early lipid utilization. After 15 d, PFOA-exposed mice exhibited decreased resting RER and suppressed active VO2, suggesting impaired circadian metabolic activation. In contrast, HFD mice maintained elevated VO2 across both resting and active cycles and showed reduced RER variation between phases, indicating metabolic inflexibility. PFOA exposure also increased relative liver weights and ACOX-1 activity. HFD resulted in an increase in body weight and increase in fat mass without hepatomegaly. These results indicate that both exposure paradigms disrupt whole-body metabolism and circadian bioenergetics. PFOA induced pronounced peroxisomal proliferation and suppressed resting-cycle energy expenditure without weight gain, whereas HFD drove obesogenic effects with impaired substrate switching. These findings provide mechanistic insight into how environmental and dietary stressors alter metabolic rhythms.