title: Epoxyeicosatrienoic Acids Regulate Adipocyte Differentiation of Mouse 3T3 Cells, Via PGC-1α Activation, Which Is Required for HO-1 Expression and Increased Mitochondrial Function.
abstract: Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered preadipocyte function, enhanced peroxisome proliferation-activated receptor γ coactivator α (PGC-1α) expression, and increased mitochondrial function in the 3T3-L1 preadipocyte subjected to adipogenesis. Cells treated with EET resulted in an increase, P < 0.05, in PGC-1α and a decrease in mitochondria-derived ROS (MitoSox), P < 0.05. The EET increase in heme oxygenase-1 (HO-1) levels is dependent on activation of PGC-1α as cells deficient in PGC-1α (PGC-1α knockout adipocyte cell) have an impaired ability to express HO-1, P < 0.02. Additionally, adipocytes treated with EET exhibited an increase in mitochondrial superoxide dismutase (SOD) in a PGC-1α-dependent manner, P < 0.05. The increase in PGC-1α was associated with an increase in β-catenin, P < 0.05, adiponectin expression, P < 0.05, and lipid accumulation, P < 0.02. EET decreased heme levels and mitochondria-derived ROS (MitoSox), P < 0.05, compared to adipocytes that were untreated. EET also decreased mesoderm-specific transcript (MEST) mRNA and protein levels (P < 0.05). Adipocyte secretion of EET act in an autocrine/paracrine manner to increase PGC-1α is required for activation of HO-1 expression. This is the first study to dissect the mechanism by which the antiadipogenic and anti-inflammatory lipid, EET, induces the PGC-1α signaling cascade and reprograms the adipocyte phenotype by regulating mitochondrial function and HO-1 expression, leading to an increase in healthy, that is, small, adipocytes and a decrease in adipocyte enlargement and terminal differentiation. This is manifested by an increase in mitochondrial function and an increase in the canonical Wnt signaling cascade during adipocyte proliferation and terminal differentiation.
authors.affiliation: 1 Department of Pharmacology, New York Medical College , Valhalla, New York.|2 Cardiac Research Laboratory, Felsenstein Medical Research Institute, Tel-Aviv University , Petah-Tikva, Israel .
authors.forename: Maayan
authors.initials: M
authors.lastname: Waldman
authors.affiliation: 1 Department of Pharmacology, New York Medical College , Valhalla, New York.
authors.forename: Lars
authors.initials: L
authors.lastname: Bellner
authors.affiliation: 1 Department of Pharmacology, New York Medical College , Valhalla, New York.|3 University of Catania , Department of Drug Science/Section of Biochemistry, Catania, Italy .
authors.forename: Luca
authors.initials: L
authors.lastname: Vanella
authors.affiliation: 1 Department of Pharmacology, New York Medical College , Valhalla, New York.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schragenheim
authors.affiliation: 4 Departments of Medicine and Surgery, Joan C. Edwards School of Medicine, Marshall University , Huntington, West Virginia.
authors.forename: Komal
authors.initials: K
authors.lastname: Sodhi
authors.affiliation: 1 Department of Pharmacology, New York Medical College , Valhalla, New York.
authors.forename: Shailendra P
authors.initials: SP
authors.lastname: Singh
authors.affiliation: 1 Department of Pharmacology, New York Medical College , Valhalla, New York.
authors.forename: Daohong
authors.initials: D
authors.lastname: Lin
authors.affiliation: 1 Department of Pharmacology, New York Medical College , Valhalla, New York.
authors.forename: Anand
authors.initials: A
authors.lastname: Lakhkar
authors.affiliation: 5 Department of Pathology, New York Medical College , Valhalla, New York.
authors.forename: Jiangwei
authors.initials: J
authors.lastname: Li
authors.affiliation: 2 Cardiac Research Laboratory, Felsenstein Medical Research Institute, Tel-Aviv University , Petah-Tikva, Israel .
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
authors.affiliation: 6 Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University , Tel Hashomer, Israel .
authors.forename: Michael
authors.initials: M
authors.lastname: Arad
authors.affiliation: 5 Department of Pathology, New York Medical College , Valhalla, New York.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Darzynkiewicz
authors.affiliation: 7 The Rockefeller University , New York, New York.
authors.forename: Atallah
authors.initials: A
authors.lastname: Kappas
authors.affiliation: 1 Department of Pharmacology, New York Medical College , Valhalla, New York.|4 Departments of Medicine and Surgery, Joan C. Edwards School of Medicine, Marshall University , Huntington, West Virginia.|7 The Rockefeller University , New York, New York.|8 Department of Medicine, New York Medical College , Valhalla, New York.
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects*; D015777:Eicosanoids / Q000494:pharmacology*; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015777:Eicosanoids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011506:Proteins; D011524:Protoporphyrins; D012333:RNA, Messenger; D051176:beta Catenin; C103637:mesoderm specific transcript protein; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1