title: Di-(2-Ethylhexyl)-Phthalate (DEHP) Causes Impaired Adipocyte Function and Alters Serum Metabolites.
abstract: Di-(2-ethylhexyl)-phthalate (DEHP), an ubiquitous environmental contaminant, has been shown to cause adverse effects on glucose homeostasis and insulin sensitivity in epidemiological studies, but the underlying mechanisms are still unknown. We therefore tested the hypothesis that chronic DEHP exposure causes impaired insulin sensitivity, affects body weight, adipose tissue (AT) function and circulating metabolic parameters of obesity resistant 129S6 mice in vivo. An obesity-resistant mouse model was chosen to reduce a potential obesity bias of DEHP effects on metabolic parameters and AT function. The metabolic effects of 10-weeks exposure to DEHP were tested by insulin tolerance tests and quantitative assessment of 183 metabolites in mice. Furthermore, 3T3-L1 cells were cultured with DEHP for two days, differentiated into mature adipocytes in which the effects on insulin stimulated glucose and palmitate uptake, lipid content as well as on mRNA/protein expression of key adipocyte genes were investigated. We observed in female mice that DEHP treatment causes enhanced weight gain, fat mass, impaired insulin tolerance, changes in circulating adiponectin and adipose tissue Pparg, adiponectin and estrogen expression. Serum metabolomics indicated a general increase in phospholipid and carnitine concentrations. In vitro, DEHP treatment increases the proliferation rate and alters glucose uptake in adipocytes. Taken together, DEHP has significant effects on adipose tissue (AT) function and alters specific serum metabolites. Although, DEHP treatment led to significantly impaired insulin tolerance, it did not affect glucose tolerance, HOMA-IR, fasting glucose, insulin or triglyceride serum concentrations. This may suggest that DEHP treatment does not cause impaired glucose metabolism at the whole body level.
authors.affiliation: IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Hesselbarth
authors.affiliation: Institute of Anatomy, University of Leipzig, Leipzig, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gericke
authors.affiliation: German Center for Diabetes Research (DZD), Leipzig, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Kunath
authors.affiliation: Institute for Clinical Chemistry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Biemann
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Rima
authors.initials: R
authors.lastname: Chakaroun
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kosacka
authors.affiliation: IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kern
authors.affiliation: IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.|Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.affiliation: Department of Anatomy and Cell Biology, Martin Luther University Halle, Halle (Saale), Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Fischer
authors.affiliation: Department of Metabolomics, Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Rolle-Kampczyk
authors.affiliation: Department of Metabolomics, Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Feltens
authors.affiliation: Department of Metabolomics, Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Otto
authors.affiliation: Department of Metabolomics, Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany.
authors.forename: Dirk K
authors.initials: DK
authors.lastname: Wissenbach
authors.affiliation: Department of Metabolomics, Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany.|Department of Proteomics, Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany.|Department of Biotechnology and Environmental Engineering, University of Aalborg, Aalborg, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: von Bergen
authors.affiliation: IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.|Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001769:Blood / Q000187:drug effects* / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004051:Diethylhexyl Phthalate / Q000378:metabolism / Q000633:toxicity*; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction
chemical_list: D004785:Environmental Pollutants; D004051:Diethylhexyl Phthalate; D005947:Glucose