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Adverse Adipose Phenotype and Hyperinsulinemia in Gravid Mice Deficient in Placental Growth Factor

Department of Obstetrics and Gynecology (B.H., R.v.B., L.V., J.V.) and the Center for Molecular and Vascular Biology (B.V.H., H.R.L.), Health Campus Gasthuisberg, Katholieke Universiteit Leuven, 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: J. Verhaeghe, M.D. Ph.D., Department of Obstetrics and Gynecology, U.Z. Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. E-mail: johan.verhaeghe{at}uz.kuleuven.be.

Pregnancy-induced metabolic changes are regulated by signals from an expanded adipose organ. Placental growth factor (PlGF), acting through vascular endothelial growth factor receptor-1, may be among those signals. There is a steep rise in circulating PlGF during normal pregnancy, which is repressed in gravidas who develop preeclampsia. PlGF-deficiency in mice impairs adipose vascularization and development. Here we studied young-adult PlGF-deficient (PlGF^–/–) and wild-type mice on a high-fat diet in the nongravid state and at embryonic day (E) 13.5 or E18.5 of gestation. Litter size and weight were normal, but E18.5 placentas were smaller in PlGF^–/– pregnancies. PlGF^–/– mice showed altered intraadipose dynamics, with the following: 1) less blood vessels and fewer brown, uncoupling protein (UCP)-1-positive, adipocytes in white sc and perigonadal fat compartments and 2) white adipocyte hypertrophy. The mRNA expression of β₃-adrenergic receptors, peroxisome proliferator-activated receptor- coactivator-1, and UCP-1 was decreased accordingly. Moreover, PlGF^–/– mice showed hyperinsulinemia. Pregnancy-associated changes were largely comparable in PlGF^–/– and wild-type dams. They included expanded sc fat compartments and adipocyte hypertrophy, whereas adipose expression of key angiogenesis/adipogenesis (vascular endothelial growth factor receptor-1, peroxisome proliferator-activated receptor-₂) and thermogenesis (β₃-adrenergic receptors, peroxisome proliferator-activated receptor- coactivator-1, and UCP-1) genes was down-regulated; circulating insulin levels gradually increased during pregnancy. In conclusion, reduced adipose vascularization in PlGF^–/– mice impairs adaptive thermogenesis in favor of energy storage, thereby promoting insulin resistance and hyperinsulinemia. Pregnancy adds to these changes by PlGF-independent mechanisms. Disturbed intraadipose dynamics is a novel mechanism to explain metabolic changes in late pregnancy in general and preeclamptic pregnancy in particular.