Mechanisms of metabolic dysfunction in the offspring of maternal obesity: role of inflammation

母亲肥胖后代代谢功能障碍的机制：炎症的作用

• 批准号: 9807710
• 负责人: Alina Maloyan
• 金额: $ 22.45万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807710
• 关键词: Address; Adipocytes; Adipose tissue; Adoptive Transfer; Adult; Affect; Age; Age-Months; Attenuated; Body Composition; Body Weight; Body fat; CD27 Antigens; CD8B1 gene; Cardiovascular Diseases; Cells; Chronic; Cleaved cell; Data; Dendritic Cells; Development; Diet; Dipeptides; Disease; Eating; Embryo; Energy Intake; Environment; FDA approved; Female; Fetus; Functional disorder; Future Generations; Generations; Health; Hepatic Tissue; Hepatocyte; High Fat Diet; Human; Immune; Immune system; Immunity; In Vitro; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Knock-out; Knockout Mice; Knowledge; Life; Link; Liver; Measures; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Monitor; Mothers; Mus; Nutrient; Obesity; Obesity Epidemic; Overweight; Pathologic; Pathway interactions; Peptide Hydrolases; Perivascular Fibrosis; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Population; Positioning Attribute; Pregnancy; Pregnant Women; Prevention; Production; Public Health; RAG1 gene; Research; Role; Serum; Surface; T memory cell; T-Lymphocyte; Testing; Therapeutic; Umbilical Cord Blood; Visceral; Visceral fat; Wild Type Mouse; Woman; adipokines; age related; cytokine; experimental study; fetal; glucose metabolism; glucose tolerance; immune activation; impaired glucose tolerance; improved; in utero; inhibitor/antagonist; male; maternal obesity; mouse model; obese mothers; offspring; prevent; programs; role model; sedentary lifestyle; sex; therapeutic target

Obesity in pregnancy predisposes the offspring to obesity, thus initiating a vicious cycle of obesity and its health-related consequences in subsequent generations. Over the past two decades, the search for a potential unifying mechanism behind obesity and its related diseases has revealed a close relationship between nutrient excess and dysfunction in immunity and inflammation. Obesity is considered a state of chronic, low-grade inflammation. The activation of pathological inflammation in obese pregnant women has been characterized, but the role of inflammation in the developmental programming of maternal obesity remains unclear. Dipeptyl peptidase 4 (DPP4) is an adipokine that is released from adipocytes, hepatocytes, and immune cells and promotes obesity by activating innate inflammation and increasing caloric intake. DPP4 expression is substantially elevated in the visceral fat of obese subjects, and serum DPP4 correlates with all parameters of metabolic syndrome. Pharmacological inhibitors of DPP4 have been effective in the prevention of insulin resistance and cardiovascular diseases. In ongoing experiments, we found that modulation of maternal immune system precedes obesity and metabolic dysfunction, suggesting that maternal inflammation and not obesity per se is the major culprit in developmental programming. We have established a mouse model of a maternal high-fat diet (HFD) and were able to recapitulate the metabolic dysfunction seen in the human offspring of obese mothers. Our preliminary data show that: 1). Three-week-old offspring of HFD-fed mothers have increased infiltrations of CD4+, CD8+, and memory T cells in the liver and visceral adipose tissue and increased body fat percentage when compared to the offspring of a regular diet (RD)-fed mothers. 2). At 8 weeks of age, mice that were born to HFD-fed mothers show increased adiposity, impaired glucose tolerance, and perivascular fibrosis despite eating a regular diet. 3). At 11 months of age, the offspring of HFD-fed mothers are obese and insulin-resistant. 4). Adoptive transfer of dendritic cells collected from the offspring of HFD- but not RD-fed mothers to naïve mice caused accumulation of adipose tissue and dysregulation of glucose metabolism. 5. DPP4 activity is increased in the plasma and cord blood from obese mothers carrying male fetuses, and in the liver of male offspring of HFD-fed mice, suggesting that DPP4 is regulated in a sex- dependent manner. The overarching hypothesis of this proposal is that maternal obesity induces hepatic and adipose tissue inflammation in offspring, thereby increasing the production of Dpp4 and the activation of inflammatory pathways leading to metabolic dysfunction. Aim 1 will test the hypothesis that T cells play a critical role in metabolic dysfunction in the offspring of HFD fed mothers. Aim 2 will test the hypothesis that DPP4 inhibition attenuates the programming effect of maternal obesity by reducing caloric intake, improving glucose tolerance, and suppressing immune activation. The proposed studies will provide fetal sex-specific, mechanistic data linking maternal inflammation and metabolic function in the offspring.

怀孕期间的肥胖会使后代容易肥胖，从而引发肥胖和肥胖的恶性循环。 在后代中产生与健康相关的后果。在过去的二十年里，对潜在的 肥胖及其相关疾病背后的统一机制揭示了营养之间的密切关系 免疫和炎症方面的过度和功能障碍。肥胖被认为是一种慢性的、低级别的状态 发炎。肥胖孕妇病理性炎症的激活已被表征， 但炎症在母体肥胖的发育规划中的作用尚不清楚。二肽基 肽酶4(DPP4)是一种脂肪因子，由脂肪细胞、肝细胞和免疫细胞释放，并 通过激活先天炎症和增加卡路里摄入量来促进肥胖。DPP4表达式为 肥胖受试者内脏脂肪显著升高，血清DPP4与 代谢综合征。DPP4的药物抑制剂在预防胰岛素方面是有效的 耐药性和心血管疾病。在正在进行的实验中，我们发现母体的调制 免疫系统先于肥胖和代谢功能障碍，表明母体炎症和非 肥胖本身是发展规划的主要罪魁祸首。我们已经建立了一个小鼠模型， 母亲的高脂肪饮食(HFD)，并能够概括人类的代谢功能障碍 肥胖母亲的后代。我们的初步数据显示：1)。喂食HFD的母亲的三周大的后代 增加了肝脏和内脏脂肪组织中CD4+，CD8+和记忆T细胞的渗透，并 与正常饮食(RD)喂养的母亲的后代相比，增加了体脂百分比。2)。在8点 几周后，喂食HFD的母亲所生的小鼠表现出肥胖增加，糖耐量受损， 和血管周围纤维化，尽管有规律的饮食。3)。在11个月大时，HFD的后代喂食 母亲肥胖且对胰岛素有抵抗力。4)。子代小鼠树突状细胞过继转移的研究 给幼鼠喂食HFD而不是RD的母亲会导致脂肪组织堆积和机体功能失调 葡萄糖代谢。5.孕期肥胖母亲血浆和脐带血中DPP4活性升高 雄性胎儿和喂食HFD的雄性后代的肝脏中，表明DPP4在一种性别- 依赖的态度。这一建议的首要假设是，母亲肥胖会导致肝脏和 子代脂肪组织炎症，从而增加DPP4的产生和激活 导致代谢功能障碍的炎症途径。目标1将检验T细胞扮演着一个 喂养HFD的母亲的后代代谢功能障碍的关键作用。目标2将检验这一假设 抑制DPP4通过减少卡路里摄入量，改善母体肥胖的程序效应 葡萄糖耐量和抑制免疫激活。拟议的研究将提供特定于胎儿性别的， 将母体炎症和子代代谢功能联系起来的机制数据。