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.

怀孕中的肥胖使后代易于肥胖，从而引发了肥胖的恶性循环 随后的后代与健康有关的后果。在过去的二十年中，寻找潜力 肥胖及其相关疾病背后的统一机制揭示了养分之间的密切关系 免疫和炎症中的过量和功能障碍。肥胖被认为是慢性低级的状态 炎。肥胖孕妇的病理炎症激活已被表征， 但是，炎症在孕产妇肥胖的发展中的作用尚不清楚。 Dipeptyl 肽酶4（DPP4）是一种脂肪因子，从脂肪细胞，肝细胞和免疫细胞以及免疫细胞以及 通过激活先天注射并增加热量摄入来促进肥胖。 DPP4表达是 肥胖受试者的内脏脂肪显着升高，血清DPP4与所有参数相关 代谢综合征。 DPP4的药理抑制剂已有效预防胰岛素 阻力和心血管疾病。在正在进行的实验中，我们发现母体的调节 免疫系统先于肥胖和代谢功能障碍，表明炎症而不是 肥胖本身是制定编程的主要罪魁祸首。我们已经建立了一个鼠标模型 母体高脂饮食（HFD），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）。三周大的HFD喂养母亲的后代 肝脏和内脏脂肪组织中的CD4+，CD8+和记忆T细胞的浸润增加了 与常规饮食（RD）母亲的后代相比，体内脂肪百分比增加。 2）。 8岁 数周大的小鼠出生于HFD喂养母亲的小鼠表明肥胖增加，葡萄糖耐受性受损， 血管周纤维化会定期吃饮食。 3）。在11个月大时，HFD喂养的后代 母亲是肥胖的，耐胰岛素。 4）。从后代收集的树突状细胞的收养转移 HFD-但不给RD喂养的母亲到幼稚的小鼠会导致脂肪组织的积累和失调 葡萄糖代谢。 5。肥胖母亲的血浆中DPP4活性增加 男性胎儿，以及HFD喂养小鼠的雄性后代的肝脏中，表明DPP4受到性别的调节 依赖方式。该提议的总体假设是孕产妇肥胖引起肝脏和 后代的脂肪组织注射，从而增加了DPP4的产生和激活 炎症途径导致代谢功能障碍。 AIM 1将检验T细胞发挥的假设 在代谢功能障碍中的关键作用在HFD Fed母亲的后代中。 AIM 2将检验以下假设 DPP4抑制作用通过减少热量摄入量来减轻孕产妇肥胖的编程效果 葡萄糖耐受性和抑制免疫激活。拟议的研究将提供特定于胎儿性别的研究 机械数据将后代中的遗产注射和代谢功能联系起来。