Phthalate exposure causes browning-like effects on adipocytes in vitro and in vivo

Mono(2-ethylhexyl)phthalate (MEHP) promotes adipogenesis via PPARγ. PPARγ agonists, e.g., rosiglitazone (RSG), enhance adipocyte browning. However, scientific evidence regarding MEHP as a browning chemical is lacking. This study combined 3T3-L1 adipocytes and C57BL/6J mice to examine the potential roles of MEHP in browning. MEHP and the browning agent RSG caused similar energy metabolism in adipocytes. Both MEHP and RSG caused transcriptional changes involved in browning-associated thermogenesis, energy homeostasis, inflammatory response, and glucose uptake. MEHP-treated adipocytes exhibited brown adipocyte-like characteristics, i.e., increased mitochondrial proton leak, triiodothyronine-induced Bmp8b expression, decreased inflammation, and smaller lipid droplets. Increased PDK4 and PEPCK1 in MEHP/RSG-treated adipocytes could block glucose utilization for mitochondrial respiration. Mitochondrial/peroxisomal biogenesis and fatty acid β-oxidation in MEHP-treated adipocytes were enhanced. Candidate genes in promoting browning of MEHP-treated adipocytes were highlighted. In di(2-ethylhexyl)phthalate (DEHP)-treated mice, transcriptional changes in white adipose tissue (WAT) were associated with adipocyte differentiation, lipid synthesis, carbohydrate uptake, and WAT/brown adipose tissue (BAT) quantity. PPARγ and NR4A1 were predicted as the top two upstream regulators in orchestrating transcriptional changes. DEHP-treated 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, supporting the browning-like effects in vivo. •MEHP and RSG cause similar energy metabolism/gene expression in adipocytes.•MEHP-treated adipocytes exhibit brown adipocyte-like characteristics.•Increased PDK4/PEPCK1 blocks glucose utilization for mitochondrial respiration.•MEHP causes enhanced mitochondrial/peroxisomal biogenesis and fatty acid oxidation.•DEHP-treated mice show the browning-associated transcriptional changes in WAT.