Role of Adipokine FABP4 in Glucoregulation and Counter Regulatory Responses

脂肪因子 FABP4 在血糖调节和反调节反应中的作用

• 批准号: 10530591
• 负责人: GOKHAN S HOTAMISLIGIL
• 金额: $ 50.48万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530591
• 关键词: Adipocytes; Adipose tissue; Animals; Antibodies; Antidiabetic Drugs; Back; Biochemical; Biological; Biological Assay; Biology; Biophysics; Cardiometabolic Disease; Cardiovascular Diseases; Cells; Circulation; Communication; Complex; Dependence; Development; Diabetes Mellitus; Endocrine; Endocrine system; Energy-Generating Resources; Exhibits; FABP4 gene; Fasting; Gene Expression; Genetic; Glucagon; Glucagon Receptor; Glucocorticoids; Glucose; Goals; Hepatic; Hepatocyte; Homeostasis; Hormonal; Hormones; Human; Hypoglycemia; Insulin; Insulin Resistance; Laboratories; Life; Link; Lipids; Liver; Mammals; Maps; Mediating; Mediator; Metabolic; Metabolic Diseases; Mission; Modeling; Molecular; Mus; Names; Nutrient; Nutrient availability; Obesity; Obesity Epidemic; Obesity associated disease; Organ; Organism; Pathogenesis; Pathology; Pathway interactions; Phenocopy; Play; Public Health; Regulation; Rest; Role; Signal Pathway; Signal Transduction; Starvation; System; Testing; Therapeutic; Time; Tissues; Triglycerides; United States National Institutes of Health; Vertebrates; Work; adipokines; blood glucose regulation; combat; diabetic; euglycemia; experimental study; fatty acid-binding proteins; gain of function; glucose metabolism; glucose production; hepatic gluconeogenesis; hormonal signals; hyperglucagonemia; in vivo; innovation; insight; member; metabolic abnormality assessment; mouse model; novel; novel therapeutic intervention; obesity development; response; therapy development; treatment strategy

PROJECT SUMMARY Despite importance of counter-regulatory mechanisms to combat starvation and hypoglycemia, a significant component of this adaptive network, adipose tissue, remains understudied. It is functionally and evolutionarily conceivable that signals must exist to integrate this major source of energy during fasting to rest of the counter- regulatory network. The major adipocyte fatty acid binding protein (FABP) member FABP4, is secreted from adipocytes circulating levels rise in fasting and in the context of obesity, and the hormone acts on the liver to promote hepatic glucose production. In this way, the high levels of circulating FABP4 that occur in obese animals appear to have an effect reminiscent of the hyperglucagonemia that characterizes the diabetic state. The objective of this proposal is to understand the contribution of circulating FABP4 in mediating aberrant hepatic gluconeogenesis in the diabetic condition. Our overarching hypothesis is that FABP4 potentiates the action of glucagon signaling and is a critical component of counter-regulatory machinery and mediator of the development of obesity-related diabetes. The studies described in the current proposal will test this hypothesis by determining whether FABP4 is required to mediate the effect of hyperglucagonemia in diabetes, by characterizing a potential FABP4-glucagon-glucagon receptor (GCGR) physical interaction, and by defining the mechanism by which the FABP4 signal is propagated in hepatocytes. These experiments will make use of genetic mouse models and biochemical and cell-based assays to dissect the function of circulating FABP4 and its interaction with the glucagon signaling pathway. This contribution is significant because it will illuminate the molecular signaling pathways that underlie the well-established connection between obesity and diabetes, and may lead to the development of novel therapeutic strategies. The innovation of this work lies in pinpointing a novel mechanism of endocrine regulation - the interaction between an adipokine and a glucoregulatory hormone that links the adipose tissue to counter-regulatory mechanisms- and carries important implications for metabolic disease pathogenesis.

项目摘要 尽管反对饥饿和低血糖症的反调节机制的重要性，但很重要 该自适应网络的组成部分，脂肪组织，仍在研究。它在功能和进化上是 可以想象必须存在信号，以将禁食过程中的这一主要能源整合到其余的反击中 监管网络。主要的脂肪细胞脂肪酸结合蛋白（FABP）成员Fabp4被分泌 脂肪细胞在禁食和肥胖的背景下循环水平上升，激素作用于肝脏以促进 肝葡萄糖产生。这样，肥胖动物中发生的高水平循环FABP4似乎 具有让人联想到糖尿病态的高葡萄糖血症的作用。这个目的 提案是了解循环FABP4在介导异常肝糖异发生中的贡献 糖尿病状况。我们的总体假设是Fabp4增强了胰高血糖素信号的作用，是一个 反调节机制的关键组成部分和与肥胖相关糖尿病发展的中介者。这 当前提案中描述的研究将通过确定是否需要Fabp4来检验这一假设 通过表征潜在的FABP4-葡萄糖 - 葡聚糖受体的表征，介导糖尿病中高葡萄糖的作用 （GCGR）物理相互作用，并通过定义在肝细胞中传播FabP4信号的机制。 这些实验将利用遗传小鼠模型以及生化和基于细胞的测定法进行剖析 循环FABP4的功能及其与胰高血糖素信号通路的相互作用。这项贡献很重要 因为它将照亮构成良好联系的分子信号通路 肥胖和糖尿病，可能导致新的治疗策略的发展。这项工作的创新 在于指出内分泌调节的新型机制 - 脂肪因子与A之间的相互作用 将脂肪组织与反调节机制联系起来的葡萄糖调节激素 - 对代谢疾病发病机理的影响。

项目成果

A hormone complex of FABP4 and nucleoside kinases regulates islet function.

• DOI: 10.1038/s41586-021-04137-3
• 发表时间: 2021-12
• 期刊: Nature
• 影响因子: 64.8
• 作者: Prentice KJ;Saksi J;Robertson LT;Lee GY;Inouye KE;Eguchi K;Lee A;Cakici O;Otterbeck E;Cedillo P;Achenbach P;Ziegler AG;Calay ES;Engin F;Hotamisligil GS
• 通讯作者: Hotamisligil GS

Endothelial-derived FABP4 constitutes the majority of basal circulating hormone and regulates lipolysis-driven insulin secretion.

• DOI: 10.1172/jci.insight.164642
• 发表时间: 2023-07-24
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Inouye, Karen E.;Prentice, Kacey J.;Lee, Alexandra;Wang, Zeqiu B.;Dominguez-Gonzalez, Carla;Chen, Mu Xian;Riveros, Jillian K.;Burak, M. Furkan;Lee, Grace Y.;Hotamisligil, Gokhan S.
• 通讯作者: Hotamisligil, Gokhan S.