Adiponectin & Resistin: Structure, Function & Effects

脂联素

基本信息

批准号：
7440170
负责人：
PHILIPP E SCHERER
金额：
$ 41.66万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-15 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7440170
关键词：
Address Adenoviruses Adipocytes Adipose tissue Adopted Affect Aging Alprostadil Animals Area Attention Authorship Behavior Biology Blood Circulation Blood Glucose Cell Nucleus Comb animal structure Complement Complex Cysteine Diabetes Mellitus Diet Disruption Disulfide Linkage Dominant-Negative Mutation Dose Endocrine Glands Endocrinology Enzymes Excision Family Fasting Fatty acid glycerol esters Funding Future Genetic Transcription Glucose Goals Grant Head Hepatic Hepatocyte Homeostasis Hormones In Vitro Individual Institution Insulin Insulin Resistance Insulin Signaling Pathway Joints Kinetics Knockout Mice Laboratories Length Link Liver Manic Manuscripts Measurement Measures Mediating Mediator of activation protein Metabolic Metabolism Minor Mitochondria Modeling Molecular Molecular Conformation Molecular Structure Monoclonal Antibody R24 New York City Non-Insulin-Dependent Diabetes Mellitus Numbers Obesity Paper Pathway interactions Perfusion Phosphoenolpyruvate Carboxylase Play Preparation Principal Investigator Process Production Protein Overexpression Proteins Published Comment Publishing Qi Regulation Relative (related person)Research Research Personnel Role Science Serum Signal Pathway Signal Transduction Solutions Structure Structure-Activity Relationship TNF gene Tail Tissues Visceral Vision Yang adipokines adiponectin cytokine dicarboxylate-binding protein dimer disulfide bond disulfide bond reduction forging forkhead protein genetic manipulation glucose output glucose production glucose-6-phosphatase hepatic gluconeogenesis in vivo insulin mediators insulin sensitivity insulin signaling loss of function mutation mutant prevent programs receptor research study resistin response secretory protein text searching tissue culture tissue/cell culture

项目摘要

DESCRIPTION (provided by applicant): Excessive hepatic glucose production is a hallmark of Type II diabetes. An important function of insulin in the liver is the suppression of hepatic glucose production. This is partly mediated via reducing the transcription of two key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6- phosphatase (G-6-Pase). Adipocyte-specific secreted molecules, termed adipokines, have highlighted the role of adipose tissue as an active endocrine organ that regulates metabolism and maintains energy homeostasis. Adiponectin has gained significant attention recently as a mediator of hepatic insulin sensitivity. In contrast, resistin has been shown to have a potent negative impact on hepatic insulin sensitivity. The ability of both of these proteins to form higher order complex structures is an essential aspect of their bioactivity that results in the modulation of the insulin-induced transcriptional changes of PEPCK and G-6-Pase, resulting in changes in hepatic glucose output. Under the auspices of this R24 application, we propose to integrate independent efforts of the four participating laboratories towards the characterization of the underlying mechanisms by which adipokines influence hepatic glucose fluxes in vivo. A detailed structure/function analysis will be performed on adiponectin and resistin to identify the critical determinants that enable these complexes to exert their effects on the downstream targets. The bioactivity of both key mediators of this process, adiponectin and resistin, is critically dependent on the formation and disruption of essential disulfide bonds, yet how the reduction of these disulfide bonds affects conformation is not clear. Metabolic clamp studies will be performed in models of impaired or increased hepatic insulin sensitivity, obtained through perfusion of adiponectin or resistin, in combination with gain- and loss-of-function mutations of potentially critical downstream targets, AMPK and Foxo1. These experiments will be complemented with similar studies in tissue culture cells. The short-term goal of this proposal is to gain a better molecular understanding of the adipo-hepatic signaling axis and how it affects glucose fluxes within the liver. The longer-term goal consists of forging closer collaborative ties between investigators in two leading Diabetes Centers in the New York City area with a vision towards much closer inter-institutional efforts in the area of obesity and diabetes research in the future.

描述（由申请人提供）：肝葡萄糖产生过多是 II 型糖尿病的标志。胰岛素在肝脏中的一个重要功能是抑制肝脏葡萄糖的产生。这部分是通过减少两种关键的糖异生酶磷酸烯醇丙酮酸羧激酶 (PEPCK) 和葡萄糖 6 磷酸酶 (G-6-Pase) 的转录来介导的。脂肪细胞特异性分泌分子，称为脂肪因子，强调了脂肪组织作为调节新陈代谢和维持能量稳态的活跃内分泌器官的作用。脂联素作为肝脏胰岛素敏感性的调节剂最近受到了极大的关注。相比之下，抵抗素已被证明对肝脏胰岛素敏感性有潜在的负面影响。这两种蛋白质形成更高阶复杂结构的能力是其生物活性的一个重要方面，可调节胰岛素诱导的 PEPCK 和 G-6-Pase 转录变化，从而导致肝葡萄糖输出的变化。在此 R24 应用的支持下，我们建议整合四个参与实验室的独立努力，以表征脂肪因子影响体内肝葡萄糖通量的潜在机制。将对脂联素和抵抗素进行详细的结构/功能分析，以确定使这些复合物能够对下游靶标发挥作用的关键决定因素。该过程的两个关键介质脂联素和抵抗素的生物活性很大程度上取决于必需二硫键的形成和破坏，但这些二硫键的还原如何影响构象尚不清楚。代谢钳研究将在肝脏胰岛素敏感性受损或增加的模型中进行，该模型是通过灌注脂联素或抵抗素，结合潜在关键下游靶点 AMPK 和 Foxo1 的功能获得和丧失突变而获得的。这些实验将得到组织培养细胞中类似研究的补充。该提案的短期目标是更好地了解脂肪肝信号轴及其如何影响肝脏内的葡萄糖通量。长期目标包括在纽约市地区两个领先的糖尿病中心的研究人员之间建立更密切的合作关系，以期未来在肥胖和糖尿病研究领域进行更密切的机构间合作。