Obesity and gestational diabetes (GDM) increase the risk of fetal overgrowth, which is associated with perinatal complications and development of metabolic syndrome in childhood or later in life. Maternal adiponectin (ADN) levels are reduced and placental nutrient transporters are up regulated in these pregnancies, however the effects of ADN on placental function are largely unknown. Our preliminary studies show that ADN regulates placental amino acid (AA) transporters. The objective of this proposal is to determine the mechanisms by which ADN regulates placental nutrient transporters and influences fetal growth. The central hypothesis is that ADN binds to the AdipoR2 in the placenta and, mediated by APPL1, activates p38MAPK and PPAR-1, which inhibit the insulin/IGF-I signaling pathway resulting in a down-regulation of nutrient transport and reduced fetal growth. Our hypothesis has been formulated on the basis of strong preliminary data demonstrating that ADN (i) inhibits insulin-stimulated AA transport, (ii) activates PPAR-1, (iii) abolishes insulin-stimulated Akt and IRS-1 phosphorylation in cultured trophoblast cells, and (iv) chronic infusions of ADN in pregnant mice inhibits the placental insulin signaling pathway and reduces fetal size. We propose three Specific Aims: (1) Determine the effects of ADN on placental nutrient transport and identify the receptors and APPL isoforms mediating these effects. We will incubate cultured human primary trophoblast cells (with and without siRNA knock-down of AdipoR1 &2 and APPL 1 &2) in physiological concentrations of ADN and/or insulin and study the activity, gene and protein expression of transporters for glucose and amino acids. (2) Identify the intracellular signaling pathways involved in mediating the effects of ADN on placental nutrient transporters. We will incubate cultured human primary trophoblast cells in ADN and/or insulin and study the phosphorylation and expression of p38MAPK, PPAR-1, IRS-1, and Akt. In cause-and-effect experiments we will transfect cultured primary human trophoblast cells with siRNA targeting key components of these signaling pathways and re-examine the effects of ADN on insulin signaling and nutrient uptake, and (3) Establish the effects of maternal ADN on placental insulin signaling, nutrient transport and fetal growth in vivo. We will infuse ADN during the last week of gestation in mice by mini- osmotic pumps. At embryonic day 18.5 we will study maternal metabolism, placental nutrient transport in vivo, placental nutrient transporter expression and placental p38MAPK, PPAR-1, IRS-1 and Akt signaling. This research is innovative because we propose a novel model where ADN, in contrast to its action in maternal peripheral tissues, causes decreased insulin sensitivity in the placenta. Furthermore, this proposal will lead to the discovery of a novel mechanism by which the endocrine functions of maternal adipose tissue influence fetal growth. This is significant because this model predicts that low maternal ADN in obesity and GDM increase placental insulin sensitivity, which contributes to enhanced placental nutrient transport and fetal growth.
Statement Fetal overgrowth is common in mothers with obesity and/or gestational diabetes, and predisposes for perinatal complications and increases the risk for her child to develop obesity, diabetes and cardiovascular disease later in life. The mechanisms underlying fetal overgrowth in these pregnancies are not fully understood and no specific treatment is available. We propose that the low maternal levels of the hormone adiponectin cause fetal overgrowth by stimulating transport of nutrients to the fetus. This new knowledge will facilitate the development of novel intervention strategies in pregnancies with fetal overgrowth with the exciting potential for adiponectin 'replacement therapy'in pregnancies complicated by gestational diabetes or obesity.
|Díaz, Paula; Powell, Theresa L; Jansson, Thomas (2014) The role of placental nutrient sensing in maternal-fetal resource allocation. Biol Reprod 91:82|
|Aye, Irving L M H; Gao, Xiaoli; Weintraub, Susan T et al. (2014) Adiponectin inhibits insulin function in primary trophoblasts by PPAR?-mediated ceramide synthesis. Mol Endocrinol 28:512-24|
|Jansson, Thomas; Powell, Theresa L (2013) Role of placental nutrient sensing in developmental programming. Clin Obstet Gynecol 56:591-601|
|Aye, I L M H; Powell, T L; Jansson, T (2013) Review: Adiponectin--the missing link between maternal adiposity, placental transport and fetal growth? Placenta 34 Suppl:S40-5|