Long-term exposure to low-dose Di(2-ethylhexyl) phthalate aggravated high fat diet-induced obesity in female mice

The potential obesogenic roles of di(2-ethylhexyl) phthalate (DEHP) have attracted great attention. The current study aimed to evaluate the combined effects of chronic low-dose DEHP (0.05 mg/kg BW) and a high-fat diet (HFD) on obesity in female mice and explore the underlying mechanisms. We found that low-dose DEHP chal-lenge for 29 weeks increased fat accumulation both in CD-and HFD-fed mice and significantly accelerated the weight gain without affecting food intake in HFD-fed mice. DEHP exposure reduced the energy metabolism, down-regulated the uncoupling protein 1 (UCP1) and total oxidative phosphorylation (OXPHOS) proteins expression in the brown adipose tissue, and up-regulated the PPAR gamma expression and its phosphorylation at Ser273 in white adipose tissue (WAT). Besides, the combination of DEHP and HFD drove the remodeling of gut microbiota of mice, characterized by the reduced richness and diversity and the elevated Firmicutes to Bacter-oidetes (F/B) ratio. Short-chain fatty acids (SCFAs) analysis revealed that DEHP and HFD cotreatment led to a decrease in levels of acetic acid, butyric acid, and pentanoic acid. Interestingly, sodium butyrate (NaB) signifi-cantly inhibited the adipogenesis and lipid accumulation of NIH/3T3 mouse embryonic fibroblasts (PPAR gamma 2 overexpression) and the PPAR gamma phosphorylation at Ser273 induced by DEHP or MEHP. These findings demon-strate that chronic low-dose DEHP challenge could prompt fat accumulation by increasing PPAR gamma phosphory-lation at Ser273 and decreasing thermogenesis in BAT, which might be associated with the SCFAs reduction.