title: Adiponectin inhibits insulin function in primary trophoblasts by PPARα-mediated ceramide synthesis.
abstract: Maternal adiponectin (ADN) levels are inversely correlated with birth weight, and ADN infusion in pregnant mice down-regulates placental nutrient transporters and decreases fetal growth. In contrast to the insulin-sensitizing effects in adipose tissue and muscle, ADN inhibits insulin signaling in the placenta. However, the molecular mechanisms involved are unknown. We hypothesized that ADN inhibits insulin signaling and insulin-stimulated amino acid transport in primary human trophoblasts by peroxisome proliferator-activated receptor-α (PPARα)-mediated ceramide synthesis. Primary human term trophoblast cells were treated with ADN and/or insulin. ADN increased the phosphorylation of p38 MAPK and PPARα. ADN inhibited insulin signaling and insulin-stimulated amino acid transport. This effect was dependent on PPARα, because activation of PPARα with an agonist (GW7647) inhibited insulin signaling and function, whereas PPARα-small interfering RNA reversed the effects of ADN on the insulin response. ADN increased ceramide synthase expression and stimulated ceramide production. C2-ceramide inhibited insulin signaling and function, whereas inhibition of ceramide synthase (with Fumonisin B1) reversed the effects of ADN on insulin signaling and amino acid transport. These findings are consistent with the model that maternal ADN limits fetal growth mediated by activation of placental PPARα and ceramide synthesis, which inhibits placental insulin signaling and amino acid transport, resulting in reduced fetal nutrient availability.
authors.affiliation: Center for Pregnancy and Newborn Research (I.L.M.H.A., T.J., T.L.P.), Department of Obstetrics and Gynecology, and Department of Biochemistry (X.G., S.T.W.), University of Texas Health Science Center San Antonio, Texas 78229.
authors.forename: Irving L M H
authors.initials: IL
authors.lastname: Aye
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gao
authors.forename: Susan T
authors.initials: ST
authors.lastname: Weintraub
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansson
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Powell
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000494:pharmacology*; D000596:Amino Acids / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008954:Models, Biological; D010088:Oxidoreductases / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D052242:Adiponectin; D000596:Amino Acids; D002518:Ceramides; D007328:Insulin; D047493:PPAR alpha; D034741:RNA, Small Interfering; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases