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; 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。 肥胖代表慢性低级组织注射的状态，有助于胰岛素抵抗（IR） 脂肪变性和2型糖尿病（T2DM）。有效治疗的要求需要改善 对疾病的理解。我们对内源性因素的理解存在很大的差距 调节炎症反应和胰岛素敏感性。在此应用中，我们表明肽， catestatin（CST），源自基因产物，Chromogranin a（CGA），直接改善脂质处置和 炎症导致肥胖小鼠模型中胰岛素抵抗（IR）的逆转。 CST改善了IR 饮食引起的肥胖（DIO）小鼠而没有减肥。我们产生了CST缺陷敲除（CST-KO）小鼠， 在正常的食物饮食中具有肥胖和胰岛素耐药性。作为可能的机制，我们的数据表明 CST通过抑制AMP - 脱氨酶（AMPD），刺激AMP依赖性激酶（AMPK）提高了AMP水平 DIO肝脏以及肝细胞培养物中的信号传导和AKT磷酸化，签署了直接的CST效应。 CST激活AMPK和AKT信号传导可通过磷酸化抑制糖异生 CRTC2和FOXO1并通过激活磷酸葡萄糖酶（PGM）升高糖原的产生。其他 CST作用的结果是在AMPK依赖性的巨噬细胞中衰减注射 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 转弯，可以增强AKT信号传导。通过肝脏部分的透射电子显微镜（TEM）分析 CST处理后，DIO小鼠的脂肪组织表明浸润或募集减少 促炎性巨噬细胞。我们假设CST抑制AMPD2的活性导致升高 AMP的水平和AMPK的激活，从而降低了脂肪变性和巨噬细胞介导的 炎症导致胰岛素信号传导的增强和抑制DIO和 CST-KO小鼠。我们将通过与两个具体目标合作来验证我们的假设：目标I。 通过抑制AMP-脱氨酶2的激活来抑制肝葡萄糖的产生 （AMPD2）提高AMPK激活所需的AMP水平。在此目标中，我们将研究 CST在肝脏和肝细胞中的CST作用机制，专注于AMPK和PGM激活。目标II。测试 CST介导的AMPK激活会导致注射抑制和葡萄糖的假设 通过增强DIO和CST-KO小鼠中AKT信号传导的生产。在此目标中，我们将分析 CST介导的AMPK激活引用的途径，导致注射和葡萄糖抑制 生产。我们将通过拆除AMPD2和AMPKα的活动以及 分析它们对CST介导的信号传导，AMP/ATP比，PGM活性，细胞因子和葡萄糖的影响 生产。通过对该建议的投资，我们相信我们将发现一种新颖的监管途径 胰岛素敏感性和葡萄糖稳态。