An anti-diabetic microRNA that promotes metabolically healthy obesity

一种抗糖尿病的 microRNA，可促进代谢健康的肥胖

基本信息

批准号：
10163161
负责人：
Sean Hartig
金额：
$ 39.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-18 至 2022-07-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163161
关键词：
Adipocytes Adipose tissue Adult Affect Antidiabetic Drugs Binding Sites Body Weight Cells Child Chronic Clinical Clinical Management Coupled Data Defect Deposition Diabetic mouse Dietary intake Energy Metabolism Exhibits Exposure to Fatty Liver Fatty acid glycerol esters Feedback Genes Genetic Genetic Transcription Glucose Goals Health High Fat Diet Homeostasis Human Impairment Incidence Individual Inflammation Inflammatory Insulin Insulin Resistance Interferons Intra-abdominal Investigation Lead Link Lipids Liver Measures Mediating Metabolic Metabolic Diseases Metabolic dysfunction MicroRNAs Molecular Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Pathway interactions Peripheral Physiological Refractory Repression Research Risk Role STAT1 gene Signal Transduction Stress Testing Therapeutic Intervention Tissue Expansion Tissues Transcriptional Regulation Transducers Transgenic Organisms United States Untranslated RNA Visceral base cell type chromatin immunoprecipitation cohort comorbidity cytokine diet-induced obesity dietary dietary excess experimental study fatty acid oxidation improved insulin sensitivity mouse model novel obese person obesity management obesity prevention preservation pressure prevent programs public health relevance subcutaneous transcription factor

项目摘要

ABSTRACT Chronic dietary energy stress on white adipose tissue (WAT) promotes fat deposition in peripheral tissues, which accelerates insulin resistance and type 2 diabetes mellitus (T2DM). Restoring the capacity of WAT to safely sequester excess energy promotes insulin sensitivity in the face of diet-induced obesity. To this end, we discovered that the microRNA miR-30a exhibits reduced expression in subcutaneous fat from diabetic mice and humans compared to normal controls. Our preliminary studies establish that miR-30a confers upon WAT the ability to withstand the pressure of high fat diet and prevent the co-morbidities of obesity. These changes result in improved whole-body insulin sensitivity coupled with muted WAT inflammation and reduced hepatic steatosis. The effect of miR-30a on WAT function coincides with complete blockade of STAT1 signaling, which is a key transducer of obesity-linked inflammatory cytokines. These exciting studies support the hypothesis that systemic insulin sensitivity is preserved by miR-30a repression of STAT1-mediated inflammation in adipocytes. Intriguingly, miR-30a confers beneficial effects on glucose and lipid homeostasis without reducing body weight. The goal of this proposal is to critically test our hypothesis by challenging our genetic mouse models of miR-30a and STAT1 expression with diet-induced obesity. In Aim 1, we will define the basis underpinning the metabolic effects of miR-30a transgenic expression in WAT. Aim 2 will evaluate the role of the inflammatory transcription factor STAT1 in mediating the metabolic effects of miR-30a expression in subcutaneous WAT. Lastly, Aim 3 will establish the mechanisms governing the transcriptional regulation of miR-30a. Our investigation of the basis by which miR-30a controls WAT function is significant because it will expand our understanding of mechanisms that connect obesity with T2DM. At the completion of our studies, we will have identified mechanisms that might be exploited in therapies to manage insulin resistance and T2DM. PUBLIC HEALTH RELEVANCE: Insulin resistance and T2DM are chronic health problems in the United States. Mechanisms that improve insulin sensitivity by restoring proper fat storage mechanisms represent new paradigms for clinical management of obesity.

抽象的白色脂肪组织（WAT）的慢性饮食能量压力会促进周围组织的脂肪沉积，加速胰岛素抵抗和 2 型糖尿病 (T2DM) 恢复 WAT 的能力。面对饮食引起的肥胖，安全测序仪多余的能量会促进胰岛素敏感性。发现 microRNA miR-30a 在糖尿病小鼠的皮下脂肪中表达减少我们的初步研究表明 miR-30a 赋予 WAT。承受高脂肪饮食压力并预防肥胖并发症的能力。改善全身胰岛素敏感性，减轻 WAT 炎症并减少肝脏 miR-30a 对 WAT 功能的影响与 STAT1 信号传导的完全阻断同时发生。是肥胖相关炎症细胞因子的关键转导因子，这些令人兴奋的研究支持了这一假设。 miR-30a 抑制 STAT1 介导的炎症，从而保留了全身胰岛素敏感性有趣的是，miR-30a 对葡萄糖和脂质稳态具有有益作用，而不降低。该提案的目标是通过挑战我们的基因小鼠来批判性地检验我们的假设。饮食诱导肥胖的 miR-30a 和 STAT1 表达模型在目标 1 中，我们将定义基础。支持 miR-30a 转基因表达在 WAT 中的代谢作用将评估 Aim 2 的作用。炎症转录因子 STAT1 介导 miR-30a 表达的代谢效应最后，目标 3 将建立控制转录调控的机制我们对 miR-30a 控制 WAT 功能的基础的研究具有重要意义，因为它将扩大我们对肥胖与 T2DM 关联机制的理解。我们将确定可用于治疗胰岛素抵抗的机制 T2DM 公共卫生相关性：胰岛素抵抗和 T2DM 是慢性健康问题。美国。通过恢复适当的脂肪储存机制来提高胰岛素敏感性的机制。新的范例代表了肥胖的临床管理。