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.

妊娠期肥胖会使后代容易肥胖，从而引发肥胖的恶性循环。 在过去的二十年里，人们一直在寻找潜在的后果。 肥胖及其相关疾病背后的统一机制揭示了营养素之间的密切关系 免疫和炎症的过度和功能障碍被认为是一种慢性、低度的状态。 肥胖孕妇病理性炎症的激活已被表征， 但炎症在孕产妇肥胖发育过程中的作用仍不清楚。 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， 通过激活先天性炎症和增加热量摄入来促进肥胖。 肥胖受试者的内脏脂肪显着升高，血清 DPP4 与所有参数相关 DPP4 的药物抑制剂可有效预防胰岛素。 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，表明母体炎症而不是 肥胖本身是发育程序的罪魁祸首。我们建立了一个小鼠模型。 母亲高脂肪饮食（HFD）并能够重现人类中观察到的代谢功能障碍 我们的初步数据表明：1). 肝脏和内脏脂肪组织中 CD4+、CD8+ 和记忆 T 细胞的浸润增加， 与常规饮食 (RD) 喂养的母亲的后代相比，体脂百分比有所增加 2)。 在几周大的时候，高脂饮食母亲所生的小鼠表现出肥胖增加、葡萄糖耐量受损、 尽管饮食正常，但仍出现血管周围纤维化 3)。 母亲肥胖且具有胰岛素抵抗 4). 收集自后代的树突状细胞。 喂养幼鼠的 HFD（而不是 RD）喂养的母亲会导致脂肪组织的积累和脂肪组织的失调。 5. 肥胖母亲的血浆和脐带血中的 DPP4 活性增加。 雄性胎儿以及 HFD 喂养小鼠的雄性后代的肝脏中，表明 DPP4 在性别调控中受到调节。 该提议的总体假设是，母亲肥胖会导致肝脏和肝脏疾病。 后代脂肪组织炎症，增加 Dpp4 的产生及其激活 目标 1 将检验 T 细胞发挥作用的假设。 目标 2 将检验以下假设： DPP4 抑制通过减少热量摄入、改善母体肥胖来减弱母体肥胖的编程效应 葡萄糖耐量和抑制免疫激活拟议的研究将提供胎儿性别特异性。 将母体炎症与后代代谢功能联系起来的机制数据。