| dc.description.abstract | Accumulating evidence has revealed the positive association between phthalate exposure and metabolic disorders, highlighting the endocrine-disrupting activity of phthalates. However, the major di‑(2‑ethylhexyl) phthalate (DEHP) metabolite MEHP has been identified as a selective PPARγ agonist. PPARγ has been reported as a potent adipocyte browning factor. Our preliminary results also demonstrated that MEHP-treated adipocytes exhibited an increased energy metabolic activity and brown adipocyte-like characteristics in vitro. By decreasing adiposity and increasing energy expenditure, the browning of white adipose tissue (WAT) is generally considered with beneficial effects on improving metabolic disorders. Considering obesity is the major risk factor for metabolic disorders, the present study aimed to investigate whether DEHP exposure caused metabolic disorders in an obesity-dependent manner. Both normal and diet-induced obese C57BL/6J mice were subjected to environmentally relevant levels of DEHP (i.e., 0.1 and 1.0 mg/kg body weight/day) by gavage for 25 weeks. DEHP-treated normal mice exhibited actively expressed browning marker genes (i.e., Pparg, Adrb1, Adrb3, Ppargc1a, and Ucp1) in WAT, increased blood FGF21 levels, and higher amounts of BAT. Meanwhile, transcriptional changes in WAT were associated with carbohydrate uptake, WAT/brown adipose tissue (BAT) quantity, and adipogenesis. Pparg and Nr4a1 were predicted as the top two upstream regulators in orchestrating transcriptional changes in WAT of DEHP-treated normal mice. The results support the browning activity of DEHP in normal mice. On the other hand, DEHP-treated obese mice exhibited higher glucose intolerance and insulin resistance than obese mice; the metabolic disorders were accompanied by increased blood levels of leptin, low-density lipoprotein (LDL), and alanine transaminase (ALT). Meanwhile, DEHP enhanced macrophage infiltration into WAT and hepatic tissue, and promoted hepatic steatosis/steatohepatitis in obese mice. Notably, the DEHP effects in obese mice were not observed in normal mice. Microarray analysis was used to determine transcriptomic changes in WAT and hepatic tissue. Results indicated that obesity and DEHP synergistically regulated carbohydrate uptake, lipolysis, and abnormality of adipose tissue, via the upstream regulators Pparg, Lipe, Cd44, and Irs1. Meanwhile, obesity and DEHP differentially modulated transcriptomic changes in hepatic tissue. Obesity was associated with lipid/cholesterol synthesis, lipid accumulation, and inflammation in hepatic tissue. In obese mice, DEHP exposure caused hepatic injury, cell migration, and changes in glycogen quantity. Microarray analysis suggested the potential mechanism underlying the early onset of metabolic disorders in DEHP-treated obese mice, supporting the endocrine-disrupting activity of DEHP in obese mice. | en_US |