Fibroblast growth factor 21 secretion enhances glucose uptake in mono(2-ethylhexyl)phthalate-treated adipocytes.

Previous studies revealed that cellular accumulation of mono(2-ethylhexyl)phthalate (MEHP) disturbed energy metabolism in adipocytes, where glucose uptake was significantly increased. The present study aimed to determine the mechanisms underlying the increased glucose uptake. MEHP-treated 3T3-L1 adipocytes exhibited a significantly increased glucose uptake activity. Immunoblot analysis suggested that the insulin-induced signals were not responsible for the increased glucose uptake. qPCR analysis revealed that both Glut1 and Glut4 genes were highly expressed during adipogenesis; Glut1 mRNA levels in MEHP-treated adipocytes were significantly increased. Moreover, MEHP-treated adipocytes exhibited significantly increased levels of fibroblast growth factor 21 (FGF21) in both mRNA and secreted protein. FGF21 is a peptide hormone with pleiotropic effects on regulation of insulin sensitivity and glucose/lipid homeostasis. We found that MEHP, FGF21, and lactate in culture medium together enhanced Fgf21 gene expression in MEHP-treated adipocytes. FGF21 signaling requires fibroblast growth factor receptor (FGFR) and ßKlotho. Fgfr family and ßKlotho genes were actively expressed during adipogenesis; mRNA levels of Fgfr3 and Fgfr4 genes in MEHP-treated adipocytes were significantly increased. Roles of FGF21/FGFR and phosphoinositide 3-kinase (PI3K)/AKT signal axes in regulation of glucose uptake were determined. We demonstrated that FGF21/FGFR signals played the major roles in up-regulation of the basal glucose uptake in MEHP-treated adipocytes. The in vitro evidence suggests that cellular FGF21 secretion enhances the basal glucose uptake in MEHP-treated adipocytes.

Estrogenic chemicals at body burden levels attenuate energy metabolism in 3T3-L1 adipocytes.

The study aimed to examine effects of environmental estrogens at body burden levels on energy metabolism in fat cells. Acclimation of T47D-KBluc cells in estrogen-deprived medium was established for high performance of estrogen-responsive luciferase reporter assay. With the assay, relative estrogenic potency of four selected estrogen receptor (ER) agonists, i.e. diethylstilbestrol, ß-estradiol, 4-nonylphenol and bisphenol A, were determined. Immunoblot analysis revealed that the ER agonists at both EC80 and EC100 caused rapid and transient phosphorylation of extracellular signal-regulated kinases (ERK) in an ER-dependent manner. 3T3-L1 adipocytes treated with the ER agonists at EC80 for 24 hours exhibited significant downregulation in mitochondrial respiration and glycolytic function. Importantly, EC80 values of 4-nonylphenol (6.0 × 10-10  m) and bisphenol A (1.0 × 10-8  m) are in the range of human body burdens. The finding that estrogenic chemicals at body burden levels cause significant impact on fat cell energy metabolism raises an important public health issue that deserves more attention.