Catestatin improves glucose homeostasis and insulin sensitivity in diet-induced obese mice

Catestatin 可改善饮食诱导的肥胖小鼠的葡萄糖稳态和胰岛素敏感性

• 批准号: 10046287
• 负责人: SUSHIL K MAHATA
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046287
• 关键词: AKT Signaling Pathway; AMP Deaminase; Adipose tissue; Affect; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Body Weight decreased; CHGA gene; CREB1 gene; Cardiovascular Diseases; Cells; Chromogranin A; Chronic; Complex; Data; Deposition; Development; Diabetes Mellitus; Diet; Disease; Dose; Endogenous Factors; FOXO1A gene; Fasting; Fatty Liver; Fatty acid glycerol esters; Gene Expression Profiling; Genes; Genetic; Gluconeogenesis; Glucose-6-Phosphate; Glycogen; Hepatic; Hepatocyte; Hypertension; Infiltration; Inflammation; Inflammatory Response; Insulin; Insulin Resistance; Investigation; Knockout Mice; Lead; Life Style; Lipids; Liver; MAPK8 gene; Mediating; Metabolic Diseases; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Occupations; Outcome; Pathway interactions; Peptides; Peripheral; Permeability; Pharmacology; Phosphorylation; Phosphotransferases; Play; Population; Production; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Regulation; STK11 gene; Signal Transduction; Stimulus; Stress; Testing; Therapeutic Agents; Tissues; Transmission Electron Microscopy; base; blood glucose regulation; combat; cytokine; diabetic; diet-induced obesity; effective therapy; gene product; glucose 1 phosphate; glucose metabolism; glucose production; glucose tolerance; improved; insulin regulation; insulin sensitivity; insulin signaling; insulin tolerance; knock-down; lipid biosynthesis; macrophage; military veteran; monocyte; mouse model; novel; obese person; recruit

Project Summary. Obesity represents a state of chronic, low-grade tissue inflammation that contributes to insulin resistance (IR) steatosis and type 2 diabetes mellitus (T2DM). The demands for effective therapy call for improved understanding of the disease. There is a significant gap in our understanding of the endogenous factors that regulate both inflammatory responses and insulin sensitivity. In this application, we showed that a peptide, catestatin (CST), derived from a gene product, chromogranin A (CgA), directly improves lipid disposal and inflammation leading to reversal of insulin resistance (IR) in a mouse model of obesity. CST improved IR in diet-induced obese (DIO) mice without weight loss. We generated CST-deficient knockout (CST-KO) mice, which are obese and insulin resistant in normal chow diet. As a possible mechanism, our data suggested that CST raised AMP levels by inhibiting AMP-deaminase (AMPD), stimulated AMP-dependent Kinase (AMPK) signaling and AKT phosphorylation in DIO liver as well as in hepatocyte cultures, signifying a direct CST effect. This activation of AMPK and AKT signaling by CST suppresses gluconeogenesis via phosphorylation of CRTC2 and FoxO1 and elevates glycogen production via activation of phosphoglucomutase (PGM). Another consequence of CST action is to attenuate inflammation, mediated by macrophages, in an AMPK-dependent manner. This is accomplished by suppressing cytokine production and proinflammatory signaling, which in turn, could enhance AKT signaling. Analysis by transmission electron microscopy (TEM) of the sections of liver and adipose tissue of DIO mice after CST treatment indicated diminished infiltration or recruitment of proinflammatory macrophages. We hypothesize that CST inhibits activity of AMPD2 giving rise to elevated level of AMP, and activation of AMPK, which in turn, reduces steatosis and macrophage-mediated inflammation leading to enhancement of insulin signaling and suppression of gluconeogenesis in DIO and CST-KO mice. We will verify our hypothesis by working with two specific aims: Aim I. To test whether CST suppresses hepatic glucose production through activation of AMPK via inhibition of AMP-deaminase 2 (AMPD2) which elevates AMP levels necessary for AMPK activation. In this aim, we will examine the mechanism of CST action in liver and hepatocyte focusing on AMPK and PGM activation. Aim II. To test the hypothesis that CST-mediated activation of AMPK leads to suppression of inflammation and glucose production via enhancement of AKT signaling in DIO and CST-KO mice. In this aim, we will analyze the pathways invoked by CST-mediated AMPK activation that lead to suppression of inflammation and glucose production. We will execute these specific aims by knocking down activities of AMPD2 and AMPKα and analyzing their impacts on CST mediated signaling, AMP/ATP ratio, PGM activity, cytokine and glucose production. Through investigation with this proposal, we believe we will discover a novel pathway for regulation of insulin sensitivity and glucose homeostasis.

项目摘要。 肥胖是一种慢性、低度组织炎症状态，导致胰岛素抵抗（IR） 脂肪变性和2型糖尿病（T2 DM）。对有效治疗的需求需要改进 了解疾病。在我们对内生因素的理解上存在着巨大的差距， 调节炎症反应和胰岛素敏感性。在这个应用中，我们发现一种肽， catestatin（CST），来源于基因产物嗜铬粒蛋白A（CgA），直接改善脂质处理， 在肥胖小鼠模型中，炎症导致胰岛素抵抗（IR）逆转。CST改善了IR， 饮食诱导的肥胖（DIO）小鼠而没有体重减轻。我们产生了CST缺陷敲除（CST-KO）小鼠， 它们在正常饮食中是肥胖和胰岛素抵抗的。作为一种可能的机制，我们的数据表明， CST通过抑制AMP脱氨酶（AMPD）、激活AMP依赖性激酶（AMPK） 在DIO肝脏以及肝细胞培养物中的信号传导和AKT磷酸化，表明直接CST效应。 CST对AMPK和AKT信号的激活通过磷酸化 CRTC 2和FoxO 1，并通过激活磷酸葡萄糖变位酶（PGM）提高糖原产量。另一 CST作用的结果是减弱炎症，由巨噬细胞介导，在AMPK依赖性 方式这是通过抑制细胞因子的产生和促炎信号传导来实现的，这在 反过来，可以增强AKT信号传导。肝脏切片的透射电镜分析 CST治疗后DIO小鼠的组织和脂肪组织表明， 促炎巨噬细胞我们假设CST抑制AMPD 2的活性，从而引起升高的 AMP水平和AMPK的活化，这反过来又减少脂肪变性和巨噬细胞介导的 炎症导致DIO中胰岛素信号传导增强和胰岛素生成抑制， CST-KO小鼠。我们将通过两个具体目标来验证我们的假设：目标I。为了测试CST是否 通过抑制AMP-脱氨酶2激活AMPK抑制肝葡萄糖生成 （AMPD 2），其提高AMPK活化所必需的AMP水平。为此，我们将研究 CST在肝脏和肝细胞中的作用机制集中于AMPK和PGM活化。Aim II.测试 假设CST介导AMPK活化导致炎症和葡萄糖抑制 通过增强DIO和CST-KO小鼠中的AKT信号传导来产生。为此，我们将分析 由CST介导的AMPK激活引起的通路，导致炎症和葡萄糖抑制 生产我们将通过敲除AMPD 2和AMPKα的活性来实现这些特定目标， 分析它们对CST介导的信号传导、AMP/ATP比值、PGM活性、细胞因子和葡萄糖的影响 生产通过对这一建议的研究，我们相信我们将发现一条新的监管途径 胰岛素敏感性和葡萄糖稳态的影响。

项目成果

Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides.

• DOI: 10.1111/apha.13655
• 发表时间: 2021-06
• 期刊: Acta physiologica (Oxford, England)
• 作者: Muntjewerff EM;Tang K;Lutter L;Christoffersson G;Nicolasen MJT;Gao H;Katkar GD;Das S;Ter Beest M;Ying W;Ghosh P;El Aidy S;Oldenburg B;van den Bogaart G;Mahata SK
• 通讯作者: Mahata SK

Gut microbiota transplantation drives the adoptive transfer of colonic genotype-phenotype characteristics between mice lacking catestatin and their wild type counterparts.

肠道微生物群移植驱动缺乏猫蛋白的小鼠与其野生型对应物之间的结肠基因型 - 表型特征的过继转移。

• DOI: 10.1080/19490976.2022.2081476
• 发表时间: 2022-01
• 期刊: GUT MICROBES
• 影响因子: 12.2
• 作者: Gonzalez-Davila, Pamela;Schwalbe, Markus;Danewalia, Arpit;Wardenaar, Rene;Dalile, Boushra;Verbeke, Kristin;Mahata, Sushil K.;El Aidy, Sahar
• 通讯作者: El Aidy, Sahar

Catestatin regulates vesicular quanta through modulation of cholinergic and peptidergic (PACAPergic) stimulation in PC12 cells.

Catestatin 通过调节 PC12 细胞中的胆碱能和肽能 (PACAPergic) 刺激来调节囊泡量子。

• DOI: 10.1007/s00441-018-2956-1
• 发表时间: 2019
• 期刊: Cell and tissue research
• 影响因子: 3.6
• 作者: Sahu,BhavaniShankar;Mahata,Sumana;Bandyopadhyay,Keya;Mahata,Manjula;Avolio,Ennio;Pasqua,Teresa;Sahu,Chinmayi;Bandyopadhyay,GautamK;Bartolomucci,Alessandro;Webster,NicholasJG;VanDenBogaart,Geert;Fischer-Colbrie,Reiner;Corti,A
• 通讯作者: Corti,A

Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion.

嗜铬粒蛋白 A 调节囊泡储存和线粒体动力学，从而影响胰岛素分泌。

• DOI: 10.1007/s00441-017-2580-5
• 发表时间: 2017
• 期刊: Cell and tissue research
• 影响因子: 3.6
• 作者: Wollam,Joshua;Mahata,Sumana;Riopel,Matthew;Hernandez-Carretero,Angelina;Biswas,Angshuman;Bandyopadhyay,GautamK;Chi,Nai-Wen;Eiden,LeeE;Mahapatra,NitishR;Corti,Angelo;Webster,NicholasJG;Mahata,SushilK
• 通讯作者: Mahata,SushilK

Catestatin as a Target for Treatment of Inflammatory Diseases.

• DOI: 10.3389/fimmu.2018.02199
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Muntjewerff EM;Dunkel G;Nicolasen MJT;Mahata SK;van den Bogaart G
• 通讯作者: van den Bogaart G