Hypoadiponectinemia and Gestational Diabetes

低脂联素血症和妊娠期糖尿病

• 批准号: 10753827
• 负责人: Jianhua Shao
• 金额: $ 48.62万
• 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 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753827
• 关键词: Adipocytes; Adverse effects; Agonist; Alpha Cell; Attenuated; Beta Cell; Blood; Cell Proliferation; Cells; Circulation; Communication; Cultured Cells; Data; Defect; Endocrine; Failure; Fatty acid glycerol esters; First Pregnancy Trimester; Functional disorder; Funding; Gene Expression; Genes; Genetic; Gestational Diabetes; Glucagon; Glucose; Health; Hormone secretion; Human; Hyperglycemia; In Vitro; Insulin; Insulin Resistance; Islet Cell; Knock-out; Mediating; Metabolic; Metabolic stress; Metabolism; MicroRNAs; Mus; Obesity; Obesity Epidemic; Organ; Pancreas; Pathologic; Pathway interactions; Placenta; Placental Lactogen; Postpartum Period; Pregnancy; Pregnancy Outcome; Prevalence; Production; Reporting; Research; Risk Factors; Role; Second Pregnancy Trimester; Structure of alpha Cell of islet; Tissues; adiponectin; conditional knockout; design; extracellular vesicles; glucagon-like peptide 1; glucose metabolism; glucose tolerance; improved; insulin secretion; islet; knockout gene; lipid metabolism; miRNA expression profiling; mouse model; offspring; paracrine; pregnant; receptor; success

SUMMARY Obesity is a key risk factor for Gestational diabetes mellitus (GDM). Due to the obesity epidemic, the prevalence of GDM has reached an alarming level. Most importantly, GDM has many adverse effects on pregnancy outcomes and postpartum maternal and offspring health. Therefore, it is urgent to elucidate the pathological mechanisms of GDM. Adiponectin is an adipocyte-secreted hormone that improves glucose and lipid metabolism. Hypoadiponectinemia before pregnancy and during the first and second trimesters strongly predicts GDM. Our studies from the previous funding period have demonstrated that adiponectin deficiency causes hyperglycemia and other metabolic abnormalities in pregnant mice. Interestingly, our studies revealed that adiponectin controls maternal metabolic adaptation by indirectly increasing β-cell proliferation and insulin production via placental lactogen (PL). However, decreased insulin secretion rates were still observed in size- matched islets from adiponectin gene knockout (Adipoq-/-) dams indicating additional mechanisms are involved besides β-cell proliferation. Extracellular vesicles (EVs) are well-conserved for intercellular and intra-organ communication. Pregnancy robustly increases EV levels in maternal circulation, partially attributed to placental- derived small EVs (psEVs). Consistent with other reports, our preliminary studies observed a stimulative effect of adiponectin on psEVs production. Importantly, psEVs enhanced glucose-induced insulin secretion of cultured islets. These data suggest that adiponectin, psEVs, and PL provide a pathway for fat/placenta/islet intra-organ crosstalk. During the last funding period, our study also identified a crucial role of pancreatic α-cells in maternal metabolic adaptation. Our study demonstrated that pregnancy increases glucagon-like peptide-1 (GLP-1) production from α-cells and then enhances maternal insulin secretion. A significant reduction of pancreatic GLP-1 was detected in Adipoq-/- dams. Notably, conditionally knocking out the adiponectin receptor 1 (AdipoR1) gene in α-cells significantly reduced GLP-1 production and glucose tolerance during pregnancy. Therefore, we hypothesize that adiponectin regulates islet adaptation to pregnancy through both fat/placenta/islet intra-organ crosstalk and intraislet paracrine. We will use genetic mouse models and human placenta and islets to 1) define the role of psEVs in adiponectin-regulated islet adaptation to pregnancy; 2) determine how adiponectin augments maternal insulin production through α-cells. The anticipated success of this project will have a significant impact on the research of maternal metabolic adaptation.

概括 肥胖是妊娠糖尿病（GDM）的关键危险因素。由于肥胖流行 GDM的患病率达到了惊人的水平。最重要的是，GDM对 怀孕结局以及产后和后代健康。因此，迫切需要阐明 GDM的病理机制。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。怀孕前以及第一和第二个三物质的低脂肪负责 预测GDM。我们从上一个资金期开始的研究表明，脂联素缺乏症 引起怀孕小鼠的高血糖和其他代谢异常。有趣的是，我们的研究表明 脂联素通过间接增加β细胞增殖和胰岛素来控制材料代谢适应 通过胎盘泌乳（PL）生产。但是，在大小 - 来自脂联素基因敲除（Adipoq - / - ）大坝的匹配胰岛表明涉及其他机制 除了β细胞增殖。细胞外蔬菜（EV）在细胞间和管道内良好 沟通。妊娠强度增加了物物循环中的EV水平，部分归因于位置 - 派生的小电动汽车（PSEV）。与其他报告一致，我们的初步研究观察到刺激效应 脂联素在PSEVS生产中的作品。重要的是，PSEV增强了葡萄糖诱导的胰岛素分泌 培养的胰岛。这些数据表明脂联素，PSEVS和PL为脂肪/pleceta/Islet提供了途径 内部串扰。在最后一个资金期间，我们的研究还确定了胰腺α细胞的关键作用 在母体代谢适应中。我们的研究表明，妊娠增加了胰高血糖素样肽-1 （GLP-1）从α细胞产生，然后增强MATER胰岛素分泌。显着减少 在Adipoq - / - 大坝中检测到胰腺GLP-1。值得注意的是，有条件敲除脂联素接收器 α细胞中的1（ADIPOR1）基因可显着降低GLP-1的产生和怀孕期间的葡萄糖耐受性。 因此，我们假设脂联素调节胰岛对怀孕的适应 脂肪/plapeta/Islet-Organ内串扰和内分泌。我们将使用遗传小鼠模型和人类 胎盘和胰岛1）定义PSEV在脂联素调节的胰岛适应妊娠中的作用； 2） 确定脂联素如何通过α细胞增强MATER胰岛素的产生。预期的成功 该项目将对孕产妇代谢适应的研究产生重大影响。

项目成果

Adiponectin Promotes Maternal β-Cell Expansion Through Placental Lactogen Expression.

脂联素通过胎盘泌乳原表达促进母体β细胞扩增。

• DOI: 10.2337/db20-0471
• 发表时间: 2021
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Qiao,Liping;Saget,Sarah;Lu,Cindy;HayJr,WilliamW;Karsenty,Gerard;Shao,Jianhua
• 通讯作者: Shao,Jianhua

High-fat feeding reprograms maternal energy metabolism and induces long-term postpartum obesity in mice.

高脂肪喂养会重新编程母体能量代谢并诱导小鼠长期产后肥胖。

• DOI: 10.1038/s41366-018-0304-x
• 发表时间: 2019
• 期刊: International journal of obesity (2005)
• 作者: Qiao,Liping;Chu,Kayee;Wattez,Jean-Sebastien;Lee,Samuel;Gao,Hongfei;Feng,Gen-Sheng;HayJr,WilliamW;Shao,Jianhua
• 通讯作者: Shao,Jianhua