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.

项目概要 尽管反监​​管机制对于对抗饥饿和低血糖非常重要，但 这种适应性网络的组成部分——脂肪组织，仍然没有得到充分研究。它在功能上和进化上 可以想象的是，必须存在信号来将禁食期间的主要能量来源整合到休息期间。 监管网络。主要脂肪细胞脂肪酸结合蛋白 (FABP) 成员 FABP4，由 禁食和肥胖背景下脂肪细胞循环水平升高，激素作用于肝脏以促进 肝葡萄糖的产生。通过这种方式，肥胖动物中出现的高水平循环 FABP4 似乎 具有让人想起糖尿病状态特征的高胰高血糖素血症的作用。此举的目的 该提案旨在了解循环 FABP4 在介导异常肝糖异生过程中的贡献 糖尿病状况。我们的首要假设是 FABP4 增强胰高血糖素信号传导的作用，并且是一种 反调节机制的关键组成部分和肥胖相关糖尿病发展的调节因素。这 当前提案中描述的研究将通过确定 FABP4 是否需要来测试这一假设 通过表征潜在的 FABP4-胰高血糖素-胰高血糖素受体介导高胰高血糖素血症对糖尿病的影响 (GCGR) 物理相互作用，并定义 FABP4 信号在肝细胞中传播的机制。 这些实验将利用基因小鼠模型以及生化和细胞分析来剖析 循环 FABP4 的功能及其与胰高血糖素信号通路的相互作用。这个贡献意义重大 因为它将阐明分子信号传导途径，这些信号传导途径构成了两者之间已建立的联系的基础 肥胖和糖尿病，并可能导致新的治疗策略的发展。本作品的创新之处 关键在于查明一种新的内分泌调节机制——脂肪因子和脂肪因子之间的相互作用 葡萄糖调节激素，将脂肪组织与反调节机制联系起来，并具有重要作用 对代谢疾病发病机制的影响。

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.