Maternal Hyperlipidemia Mediates Elevated Blood Pressure in Offspring Associated with Reprogramming Leptin Levels

Abstract

Background: Abnormal gestation energy metabolism is linked to major adult diseases in offspring. The aim of this study is to investigate whether leptin, as a mediator of energy metabolism, is involved in reprogramming the blood pressure control in offspring of mother with gestational hyperlipidemia. Methods: Third trimester serum lipid profiles were analyzed in 2687 Han Chinese women. Leptin levels were examined in newborns and preschool aged offspring. 4863 Han Chinese people, including 1784 children and 3079 adults, were recruited for the evaluation of association between birth weight and blood pressure. A high-fat-diet (HFD) pregnant rat model was also established. Results: Children born to gestational hypertriglyceridemia presented significantly higher rates of neonatal macrosomia and elevated serum leptin levels after birth. Leptin levels in both newborns and preschool age children were positively correlated with maternal triglyceride levels. Adults who were macrosomic at birth had increased blood pressures and higher incidence rates of hypertension though their BMIs had returned to normal. In rat, higher maternal lipid levels linked to sustained elevated leptin levels in offspring and were associated with increased blood pressure even with normal body weight. High maternal lipid profile induced leptin promoter hypomethylation and up-regulation of TET1, both in rat adipose tissues and lymphocytes as well as in human lymphocytes. Treatment of mesenchymal stem cells with free fatty acid during adipogenic differentiation also resulted in increased leptin and TET1 expression as well as leptin promoter hypomethylation. Interpretation: Maternal hyperlipidemia during pregnancy mediates elevated blood pressure in offspring via reprogramming leptin levels. Trial Registration: The Chinese Clinical Trial Registry (ChicCTR-OCH-14004536). Funding Statement: This study was funded by The National Key Research and Development Program of China (2017YFC1001303 to H.F.H), National Natural Science Foundation of China (81801541 to D.D.W and 81601238 to L.G), International Cooperation Project of China and Canada NSFC (81661128010 to H.F.H), and the Chinese National Key Research and Development Award (2018YFC1004600 to L.J.M). Declaration of Interests: The authors state that they have no conflict of interest to disclose. Ethics Approval Statement: The study was a hospital-based cross-section study approved by the Research and Ethics Committee of the University Hospital of China, and informed consent from each participant was obtained. Animal care and management were in accordance with the institutional guidelines for laboratory animals established by the Animal Care and Use Committee (ACUC), and were approved by the ACUC, School of Medicine, Zhejiang University, Hangzhou, China.