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Mechanisms for activation of beige adipose tissue in humans

人体米色脂肪组织的激活机制

基本信息

批准号：
10308496
负责人：
Philip A Kern
金额：
$ 60.91万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10308496
关键词：
Adipocytes Adipose tissue Adrenergic Agonists Adrenergic Receptor Affect Agonist Antidiabetic Drugs Beta Cell Biochemical Bladder Body Weight decreased Brown Fat Cell physiology Cells Chronic Conditioned Culture Media Consumption Development Diabetes Mellitus Elderly Epidemic FDA approved Fatty acid glycerol esters Fiber Fibrosis Gene Expression Glucose Glycosylated hemoglobin A Health Homeostasis Human In Vitro Inflammation Insulin Insulin Resistance Lipids Lipolysis Mammals Measures Mediating Metabolic Metabolic syndrome Methods MicroRNAs Mus Muscle Muscle Cells Muscle function Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Overactive Bladder Participant Peripheral Pharmaceutical Preparations Pharmacology Physiological Placebo Control Plasma Play Prediabetes syndrome Property Proteins Research Research Project Grants Rodent Role Skeletal Muscle Smooth Muscle Structure of beta Cell of islet Therapeutic Thinness Tissues Volatile Fatty Acids adipokines adult obesity bile acid metabolism blood glucose regulation cell type clinically relevant combat design diabetic exosome fighting glucose metabolism glucose tolerance glucose uptake human study improved improved functioning insulin secretion insulin sensitivity interest mRNA Expression new therapeutic target novel strategies obesity treatment oral glucose tolerance overtreatment prevent randomized trial response subcutaneous transcriptome sequencing uncoupling protein 1

项目摘要

We have been studying subcutaneous white adipose tissue (SC WAT) beiging in response to mirabegron, which is a β3 adrenergic receptor (β3AR) agonist. β3ARs are found in adipocytes and smooth muscle, and mirabegron is an FDA approved drug for overactive bladder. Treatment of obese, insulin resistant humans for twelve weeks with mirabegron consistently induced SC WAT beiging and this led to improved oral glucose tolerance and a lower HbA1c. The mechanism for improved glucose homeostasis involved both a small improvement in insulin sensitivity and a significant improvement in β-cell function (insulin secretion) along with an increase in muscle oxidative type 1 fibers; however, there was no weight loss or induction of brown fat. Since pancreatic β-cells and muscle do not express the β3AR, the beneficial effects of mirabegron in these cells likely occurred by an indirect mechanism. The physiological effects of mirabegron are likely mediated in part by the induction of beige adipose, which represents a metabolic sink for glucose and lipids and which may alter adipose remodeling. In addition, the changes in adipose tissue and other organs may result in secondary effects that target other tissues. Specific Aim 1. To examine the effects of the β3 agonist mirabegron on glucose metabolism, we will comprehensively analyze glucose tolerance, insulin sensitivity, and β-cell function in prediabetic subjects in a 4-month, placebo-controlled, randomized trial. We will assess changes in adipose tissue including beiging, inflammation, fibrosis, and insulin-stimulated glucose uptake by adipocytes. We will also fully characterize gene expression in SC WAT by RNA-seq to identify potential mechanisms such as altered adipokine profiles. Specific Aim 2. We hypothesize that mirabegron causes cells that express the β3AR to change the levels of secreted factors that affect peripheral cell types such as β-cells and muscle. We will use biochemical and pharmacological approaches to identify the mechanism by which conditioned medium from mirabegron-treated adipocytes increases PGC1α expression in muscle in vitro. We will utilize unbiased approaches to identify changes in lipids, metabolites, and exosome miRNA composition in the adipocyte conditioned media. We will use these approaches to identify molecules altered in plasma by mirabegron treatment that are responsible for the improvement in β-cell and muscle function. Clinical relevance: Mirabegron treatment has positive effects on glucose tolerance due to improvements in insulin sensitivity and β-cell function. This may be exploited to prevent conversion of prediabetes to diabetes or used as a therapeutic in diabetics. This application will also increase our understanding of the mechanism(s) by which mirabegron acts, which may reveal new therapeutic targets

我们一直在研究皮下白色脂肪组织（SC WAT）对mirabegron的反应，