Anthocyanins, Macronutrient Utilization and Insulin Sensitivity

花青素、大量营养素的利用和胰岛素敏感性

基本信息

批准号：
7846894
负责人：
James P DeLany
金额：
$ 25.9万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7846894
关键词：
ADD-1 protein Affect Animal Experimentation Animals Anthocyanins Appearance Atherosclerosis Berry Binding Proteins Bioflavonoid Biological Biological Assay Body fat Botanicals Carbohydrates Cell Culture System Cell Culture Techniques Cells Clinical Medicine Complication Data Development Diet Dose Energy Metabolism Fatty Acids Fatty acid glycerol esters Fruit Gene Expression Gene Expression Regulation General Population Genes Glucose Glycogen Glycosides Grapes Heart Hepatic High Pressure Liquid Chromatography Hormones Indirect Calorimetry Individual Insulin Insulin Receptor Insulin Resistance Label Laboratories Ligands Lipids Liver Long-Term Effects Macronutrients Nutrition Measures Mediating Messenger RNA Metabolic Metabolic Pathway Metabolic syndrome Metabolism Modeling Molecular Mus Muscle Myocardium Nuclear Nuclear Receptors Nutritional PPAR alpha PPAR delta PPAR gamma Pathway interactions Pattern Peripheral Peroxisome Proliferator-Activated Receptors Phenotype Phosphorylation Pigmentation physiologic function Preparation Principal Investigator Proteins Radioisotopes Receptor Signaling Regulatory Element Reporter Research Research Design Series Serum Sterols Supplementation Tissues Toxic effect Transcription factor genes Translating Triglycerides Western Blotting Work absorption adiponectin cardiovascular risk factor design dietary supplements fatty acid metabolism fatty acid oxidation feeding improved in vivo insight insulin sensitivity insulin signaling mouse model novel strategies oxidation programs receptor response sugar therapy development tissue culture transcription factor uptake

项目摘要

Insulin resistance is a key pathophysiologic feature of the "metabolic syndrome" and is strongly associated with co-existing cardiovascular risk factors and accelerated atherosclerosis. Strategies to improve insulin resistance by pharmacological means have represented the traditional approach for clinical medicine. However, because of the widespread use of dietary supplements by the general public, nutritional supplementation with the use of botanicals that increase insulin sensitivity represent an attractive and novel approach for intervention of the development of metabolic syndrome. Results of our hypothesis generating studies in mice suggest that anthocyanin supplementation may increase insulin sensitivity and decrease ectopic fat. Genes involved in carbohydrate and fatty acid metabolism were altered in the liver, consistent with increased insulin sensitivity. In the heart, genes involved in fatty acid uptake and oxidation were increased, consistent with increased peripheral fatty acid utilization. Furthermore, the pattern of gene expression observed in our preliminary studies suggests involvement of specific transcription factors including, but not limited to sterol regulatory element binding protein-1c, PPAR-gamma coactivatory-1alpha and -1beta. Finally, tissue culture studies (3T3-L1) demonstrated that anthocyanins reverse the fatty acid mediated suppression of insulin signaling, glycogen accumulation and adiponectin secretion. We hypothesize that anthocyanins, through modulation of the activities of specific transcription factors such as liver x-receptor, peroxisome proliferators activated receptors (PPARalpha, PPARdelta, PPARgamma), sterol regulatory element binding protein (SREBP)-1c, PPARgamma coactivator-1alpha and -1beta, increase the peripheral oxidation of fatty acids and thereby decrease ectopic fat accumulation in muscle and liver, affect insulin signaling, and improve overall insulin sensitivity. We propose to conduct a series of animal and cell culture studies designed to critically evaluate this overall hypothesis and its corollaries. Our specific aims are as follows: 1) To examine the in vivo effects of a semipurified grape anthocyanin preparation on insulin sensitivity, energy expenditure, fatty acid and carbohydrate oxidation and disposal, and tissue lipid accumulation in a mouse model of insulin resistance; 2) To evaluate the effects of a semipurified grape anthocyanin preparation on transcription factors, gene expression levels, protein abundance, intracellular pathways of insulin receptor signaling, and substrate metabolism in relevant cell culture models. 3) To identify the active component(s) within the anthocyanin preparation responsible for the observed changes in gene expression and substrate metabolism. Thus, our research plan is designed to comprehensively evaluate the effect of anthocyanins on pathogenic mechanisms leading to the development of insulin resistance and metabolic syndrome, and evaluates the cellular mechanisms of action for their effects.

胰岛素抵抗是“代谢综合征”的一个关键病理生理学特征，与共存的心血管危险因素和加速动脉粥样硬化密切相关。通过药理学手段改善胰岛素抵抗的策略代表了临床医学的传统方法。然而，由于公众广泛使用膳食补充剂，使用植物性营养补充剂增加胰岛素敏感性是干预代谢综合征发展的一种有吸引力且新颖的方法。我们的假设在小鼠中进行的研究结果表明，补充花青素可以提高胰岛素敏感性并减少异位脂肪。肝脏中参与碳水化合物和脂肪酸代谢的基因发生了改变，这与胰岛素敏感性的增加一致。在心脏中，涉及脂肪酸摄取和氧化的基因增加，这与外周脂肪酸利用率的增加一致。此外，我们初步研究中观察到的基因表达模式表明特定转录因子的参与，包括但不限于甾醇调节元件结合蛋白-1c、PPAR-gamma coactivatory-1alpha 和-1beta。最后，组织培养研究 (3T3-L1) 表明，花青素可以逆转脂肪酸介导的胰岛素信号传导、糖原积累和脂联素分泌的抑制。我们假设花青素通过调节特定转录因子（如肝脏 x 受体）的活性，过氧化物酶体增殖物激活受体（PPARα、PPARδ、PPARgamma）、甾醇调节元件结合蛋白（SREBP）-1c、PPARgamma 共激活剂-1α 和 - 1β，增加脂肪酸的外周氧化，从而减少肌肉和肝脏中的异位脂肪积累，影响胰岛素信号传导，并提高整体胰岛素敏感性。我们建议进行一系列动物和细胞培养研究，旨在批判性地评估这一总体假设及其推论。我们的具体目标如下： 1) 在胰岛素抵抗小鼠模型中，研究半纯化葡萄花青素制剂对胰岛素敏感性、能量消耗、脂肪酸和碳水化合物氧化和处理以及组织脂质积累的体内影响； 2) 评估半纯化葡萄花青素制剂对相关细胞培养模型中转录因子、基因表达水平、蛋白质丰度、胰岛素受体信号传导的细胞内途径和底物代谢的影响。 3) 鉴定花青素制剂中导致观察到的基因表达和底物代谢变化的活性成分。因此，我们的研究计划旨在全面评估花青素对导致胰岛素抵抗和代谢综合征发生的致病机制的影响，并评估其作用的细胞机制。