Control of glucose homeostasis through the insulin-independent Isthmin pathway

通过不依赖胰岛素​​的 Isthmin 通路控制葡萄糖稳态

• 批准号: 10633205
• 负责人: Katrin Jennifer Svensson
• 金额: $ 46.95万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633205
• 关键词: Address; Adipocytes; Adipose tissue; Animals; Biochemical; Biological; Blood Glucose; Cardiovascular Diseases; Cell Surface Receptors; Chronic; Complement; Data; Diabetes Mellitus; Endocrine; Energy Metabolism; Engineering; Fatty acid glycerol esters; Genetic; Glucose; Glucose tolerance test; Goals; High Fat Diet; Homeostasis; Hormonal; Hormones; Human; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Knockout Mice; Liver; Maintenance; Mammals; Mediating; Mediator; Medical; Metabolic; Metabolic dysfunction; Methods; Molecular; Monitor; Mus; Muscle; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Outcome; PI3K/AKT; Pathway interactions; Pharmacological Treatment; Physical activity; Physiological; Physiology; Play; Polypeptide Hormones; Proteins; Proteomics; Public Health; Receptor Protein-Tyrosine Kinases; Recombinant Proteins; Recombinants; Reproducibility; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Surface; Therapeutic; Therapeutic Agents; Tissues; Weight Gain; adipokines; blood glucose regulation; clinical application; combat; diabetic; euglycemia; expression vector; feeding; glucose metabolism; glucose uptake; hormonal signals; improved; in vivo; innovation; insight; insulin sensitivity; metabolic phenotype; multidisciplinary; mutant; novel; novel therapeutic intervention; novel therapeutics; obesity treatment; overexpression; pharmacologic; receptor; therapeutic target; tool; translation to humans; translational potential

PROJECT SUMMARY Chronic metabolic dysfunction has emerged as one of the most severe medical problems worldwide, leading to increases in type 2 diabetes, insulin resistance, and cardiovascular disease. The discovery of alternative pathways to regulate whole-body glucose and energy metabolism is urgently needed to address this great medical need. Such pathways could be exploited for new therapeutic strategies to combat diabetes and insulin resistance. Using a multidisciplinary strategy combining computational, cellular, and in vivo approaches, we have recently uncovered a new adipokine from thermogenic adipose, Isthmin-1 (Ism1), that acts to promote glucose uptake in mouse and human adipocytes. The action of Ism1 requires PI3K/AKT signaling but is entirely independent of the insulin receptor. In animals rendered diabetic by high-fat diet feeding, administration of recombinant Ism1 protein or genetic elevation of circulating Ism1 improves glucose homeostasis. However, more studies are needed in order to understand the contribution of Ism1 to glucose metabolism, and to leverage this understanding for therapeutic purposes. The overall objectives in this proposal are to establish how Ism1 can control blood glucose by determining the signaling effectors and cell surface receptor that mediate the action, determine the endogenous physiological function for Ism1, and evaluate the pharmacological potential of Ism1 as a therapeutic target. In Aim 1, we will utilize biochemical, genetic, and proteomic methods to identify the signaling pathways and cell surface receptor responsible for the signaling action and glucoregulatory mechanisms of Ism1. These studies will identify Ism1’s mechanism of action and will be critical for our understanding of Ism1 signaling as an insulin-independent pathway to regulate glucose uptake. In Aim 2, we will determine the physiological function for Ism1 using our generated whole-body and adipocyte-specific Ism1 knockout mice. These studies are essential in determining the endogenous role of Ism1 in glucose metabolism. In Aim 3, we will determine the minimal requirements for Ism1 bioactivity by generating fragments, mutants, and engineered forms of Ism1. This aim will pave the way for further optimization of a polypeptide hormone as a therapeutic agent, and will be essential in understanding the effects of augmentation of this novel pathway physiology. These contributions are expected to be significant because pathways that can regulate glucose independently of insulin will open entirely new avenues to overcome insulin resistance and diabetes, which could have a significant public health impact.

项目概要 慢性代谢功能障碍已成为全球最严重的医学问题之一，导致 2 型糖尿病、胰岛素抵抗和心血管疾病的增加。替代方案的发现 迫切需要调节全身葡萄糖和能量代谢的途径来解决这一重大问题 医疗需要。此类途径可用于对抗糖尿病和糖尿病的新治疗策略 胰岛素抵抗。采用结合计算、细胞和体内的多学科策略 最近，我们从产热脂肪中发现了一种新的脂肪因子 Isthmin-1 (Ism1)， 促进小鼠和人类脂肪细胞的葡萄糖摄取。 Ism1 的作用需要 PI3K/AKT 信号传导，但完全独立于胰岛素受体。在因高脂肪饮食而患糖尿病的动物中 喂养、施用重组 Ism1 蛋白或循环 Ism1 基因升高可改善 葡萄糖稳态。然而，需要更多的研究来了解 Ism1 对 葡萄糖代谢，并将这种理解用于治疗目的。总体目标 该提案旨在确定 Ism1 如何通过确定信号效应器来控制血糖 介导作用的细胞表面受体，确定 Ism1 的内源性生理功能，以及 评估 Ism1 作为治疗靶点的药理学潜力。在目标 1 中，我们将利用生化、 遗传和蛋白质组学方法来识别负责的信号传导途径和细胞表面受体 Ism1 的信号传导作用和葡萄糖调节机制。这些研究将确定 Ism1 的机制 的作用，对于我们理解 Ism1 信号传导作为一种独立于胰岛素的途径至关重要 调节葡萄糖的摄取。在目标 2 中，我们将使用我们生成的数据来确定 Ism1 的生理功能 全身和脂肪细胞特异性 Ism1 敲除小鼠。这些研究对于确定 Ism1 在葡萄糖代谢中的内源性作用。在目标 3 中，我们将确定以下方面的最低要求： Ism1 通过生成 Ism1 片段、突变体和工程形式来发挥生物活性。这一目标将为 进一步优化多肽激素作为治疗剂的方法，并且对于 了解增强这种新途径生理学的效果。这些贡献是 预计意义重大，因为可以独立于胰岛素调节葡萄糖的途径将会打开 克服胰岛素抵抗和糖尿病的全新途径，可能会引起广泛关注 健康影响。

项目成果

G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis.

• DOI: 10.1038/s41467-022-35069-9
• 发表时间: 2022-12-01
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Bielczyk-Maczynska, Ewa;Zhao, Meng;Zushin, Peter-James H.;Schnurr, Theresia M.;Kim, Hyun-Jung;Li, Jiehan;Nallagatla, Pratima;Sangwung, Panjamaporn;Park, Chong Y.;Cornn, Cameron;Stahl, Andreas;Svensson, Katrin J.;Knowles, Joshua W.
• 通讯作者: Knowles, Joshua W.

Isolation, culture, and functional analysis of hepatocytes from mice with fatty liver disease.

• DOI: 10.1016/j.xpro.2020.100222
• 发表时间: 2020-12-18
• 期刊: STAR protocols
• 作者: Jung Y;Zhao M;Svensson KJ
• 通讯作者: Svensson KJ

A single-cell CRISPRi platform for characterizing candidate genes relevant to metabolic disorders in human adipocytes.

用于表征与人类脂肪细胞代谢紊乱相关的候选基因的单细胞 CRISPRi 平台。

• DOI: 10.1152/ajpcell.00148.2023
• 发表时间: 2023
• 期刊: American journal of physiology. Cell physiology
• 作者: Bielczyk-Maczynska,Ewa;Sharma,Disha;Blencowe,Montgomery;SalibaGustafsson,Peter;Gloudemans,MichaelJ;Yang,Xia;Carcamo-Orive,Ivan;Wabitsch,Martin;Svensson,KatrinJ;Park,ChongY;Quertermous,Thomas;Knowles,JoshuaW;Li,Jiehan
• 通讯作者: Li,Jiehan

Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1.

• DOI: 10.7554/elife.80014
• 发表时间: 2022-09-28
• 期刊: eLife
• 影响因子: 7.7
• 作者: Zhao M;Banhos Danneskiold-Samsøe N;Ulicna L;Nguyen Q;Voilquin L;Lee DE;White JP;Jiang Z;Cuthbert N;Paramasivam S;Bielczyk-Maczynska E;Van Rechem C;Svensson KJ
• 通讯作者: Svensson KJ

A class of secreted mammalian peptides with potential to expand cell-cell communication.

一类分泌的哺乳动物肽，具有扩大细胞间通讯的潜力。

• DOI: 10.1101/2023.06.02.543503
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Wiggenhorn,AmandaL;Abuzaid,HindZ;Coassolo,Laetitia;Li,VeronicaL;Tanzo,JuliaT;Wei,Wei;Lyu,Xuchao;Svensson,KatrinJ;Long,JonathanZ
• 通讯作者: Long,JonathanZ