Adiponectin inhibits insulin function in primary trophoblasts by PPARα-mediated ceramide synthesis

Irving L M H Aye, Xiaoli Gao, Susan E Weintraub, Thomas Jansson, Theresa L. Powell

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)512-524
Number of pages13
JournalMolecular Endocrinology
Volume28
Issue number4
DOIs
StatePublished - 2014

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Peroxisome Proliferator-Activated Receptors
Ceramides
Adiponectin
Trophoblasts
Insulin
Amino Acids
Fetal Development
Mothers
Food
p38 Mitogen-Activated Protein Kinases
Birth Weight
Placenta
Small Interfering RNA
Adipose Tissue
Down-Regulation
Phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology
  • Medicine(all)

Cite this

Adiponectin inhibits insulin function in primary trophoblasts by PPARα-mediated ceramide synthesis. / Aye, Irving L M H; Gao, Xiaoli; Weintraub, Susan E; Jansson, Thomas; Powell, Theresa L.

In: Molecular Endocrinology, Vol. 28, No. 4, 2014, p. 512-524.

Research output: Contribution to journalArticle

Aye, Irving L M H ; Gao, Xiaoli ; Weintraub, Susan E ; Jansson, Thomas ; Powell, Theresa L. / Adiponectin inhibits insulin function in primary trophoblasts by PPARα-mediated ceramide synthesis. In: Molecular Endocrinology. 2014 ; Vol. 28, No. 4. pp. 512-524.
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