Hypoadiponectinemia and Gestational Diabetes

低脂联素血症和妊娠期糖尿病

• 批准号: 10063518
• 负责人: Jianhua Shao
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063518
• 关键词: ATF2 gene; Adipocytes; Adipose tissue; Adverse effects; Attention; Attenuated; B Cell Proliferation; Beta Cell; Blood; Body Weight; Data; Defect; Development; Elderly; Elements; Endocrine Glands; Energy Metabolism; Enzymes; Exhibits; Fatty acid glycerol esters; Female; Fetal Weight; Fetus; First Pregnancy Trimester; Genetic Transcription; Gestational Diabetes; Glucose; Glucose Intolerance; Glucose tolerance test; Health; High Prevalence; Hormones; Human; Hyperlipidemia; Impairment; Injections; Insulin; Insulin Resistance; Knockout Mice; Late pregnancy; Liver; Mediating; Metabolic; Metabolism; Molecular Biology; Mothers; Mus; Neurons; Nonesterified Fatty Acids; Obesity; Obesity Epidemic; Outcome; Partner in relationship; Peripheral; Phosphorylation; Play; Post-Translational Protein Processing; Postpartum Period; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Prevalence; Prolactin; Proliferation Marker; Proteins; Proto-Oncogene Proteins c-akt; Research; Risk Factors; Role; Second Pregnancy Trimester; Series; Serotonergic System; Serotonin; Signal Transduction; Skeletal Muscle; Streptozocin; TPH2; Tissues; Triglycerides; Tryptophan 5-monooxygenase; Variant; Viral Vector; Wild Type Mouse; adiponectin; early pregnancy; feeding; gestational weight gain; glucose metabolism; improved; in vivo bioluminescence imaging; insight; insulin sensitivity; islet; knockout gene; lipid metabolism; metabolic phenotype; mouse model; novel; offspring; predictive marker; pregnant; promoter; receptor; reconstitution; success

Gestational diabetes mellitus (GDM) is getting more attention due to its high prevalence and adverse effects on gestational outcomes and offspring health in later life. Obesity is a key risk factor of GDM. Adipose tissue is not only metabolically active but also an endocrine organ. Adiponectin is an adipocyte-secreted hormone that improves glucose and lipid metabolism. Hypoadiponectinemia is widely observed in GDM and/or pregnant women with obesity. More importantly, human studies have demonstrated that hypoadiponectinemia before pregnancy and during the first and second trimesters strongly predicts GDM in later pregnancy. However, there is no experimental evidence verifying the causal relationship between hypoadiponectinemia and GDM. By crossing adiponectin gene knockout (Adipoq-/-) and wild-type (WT) mice, we recently created pregnant mouse models with or without adiponectin deficiency while all fetuses were genetically identical. Despite no difference in maternal body weight and adiposity, the main hallmarks of GDM, including glucose intolerance, hyperlipidemia, insulin insufficiency and increased fetal body weight, were observed in Adipoq-/- dams at late pregnancy. Viral vector-mediated adiponectin reconstitution attenuated these metabolic phenotypes in Adipoq-/- dams. Interestingly, no significant decrease in insulin sensitivity was detected in either peripheral tissues or liver of Adipoq-/- dams. However, low levels of blood insulin and reduced β-cell mass were detected in Adipoq-/- dams. Most importantly, the above described metabolic defects were not observed in virgin Adipoq-/- mice. Our preliminary studies suggested that adiponectin enhances prolactin-induced β-cell proliferation by increasing tryptophan hydroxylase 1 (TPH1) gene transcription and serotonin expression. Therefore, the available information and our preliminary data led us to hypothesize that adiponectin plays an important role in pregnancy-induced compensatory β-cell expansion by enhancing TPH1/serotonin pathway. Hypoadiponectinemia impairs maternal glucose and lipid metabolism through inadequate β-cell expansion and insulin insufficiency. A series of mouse studies is proposed under 2 specific aims. Specific aim 1 will determine the role of adiponectin in pregnancy-induced adaptive β-cell expansion and if hypoadiponectinemia impairs maternal metabolism through insulin insufficiency. Specific aim 2 will investigate the underlying mechanisms through which adiponectin enhances pregnancy-induced β-cell expansion. The expected results of this proposal will demonstrate the causal role of hypoadiponectinemia in the development of metabolic defects during pregnancy. The anticipated success of this project will have a significant impact on the research of maternal metabolic adaptation during normal pregnancy and GDM.

妊娠糖尿病（GDM）由于其高患病率和 后来对妊娠结局和后代健康的不利影响。肥胖是关键风险 GDM的因素。脂肪组织不仅具有代谢活性，而且是内分泌器官。 脂联素是一种脂肪细胞分泌的激素，可改善葡萄糖和脂质代谢。 在GDM和/或肥胖症孕妇中广泛观察到低脂肪核苷酸血症。更重要的是， 人类的研究表明，怀孕前和第一个期间的低脂肪负责 - 第二孕期强烈预测GDM在后来的怀孕中。 但是，没有实验证据来验证因果关系 低脂肪核能血症和GDM。通过跨越脂联素基因敲除（Adipoq - / - ）和野生型（WT） 小鼠，我们最近创建了有或没有脂联素缺乏症的怀孕鼠标模型， 胎儿在​​遗传上是相同的。 尽管母体体重和肥胖没有差异，但GDM的主要标志，包括 葡萄糖摄入剂，高脂血症，胰岛素不足和胎儿体重增加，是 怀孕晚期在adipoq - / - 大坝中观察到。病毒载体介导的脂联素的重建 在adipoq - / - 大坝中减弱了这些代谢表型。有趣的是，没有显着减少 在adipoq - / - 大坝的外周组织或肝脏中检测到胰岛素敏感性。然而， 在adipoq - / - 大坝中检测到低水平的血液胰岛素和降低的β细胞质量。最多 重要的是，在Virgin Adipoq - / - 小鼠中未观察到上述代谢缺陷。我们的 初步研究表明，脂联素通过 增加色氨酸羟化酶1（TPH1）基因转录和5-羟色胺表达。 因此，可用的信息和我们的初步数据使我们假设 脂联素通过增强妊娠诱导的补偿性β细胞扩张起着重要作用 TPH1/5-羟色胺途径。低脂肪负责通过通过 β细胞扩张不足和胰岛素不足。在下面提出了一系列小鼠研究 2个具体目标。具体目标1将确定脂联素在妊娠诱导的作用 自适应β细胞的扩张和如果低脂肪膜血症会损害通过胰岛素的材料代谢 不足。特定目标2将研究脂联素的潜在机制 增强妊娠诱导的β细胞扩张。该提案的预期结果将证明 低磷灰负素血症在怀孕期间代谢缺陷发展中的因果作用。 该项目的预期成功将对孕产妇的研究产生重大影响 正常怀孕和GDM期间的代谢适应性。