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：
10531210
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/10531210
关键词：
Adipocytes Adipose tissue Adrenergic Agonists Adrenergic Receptor Affect Agonist Antidiabetic Drugs Beta Cell Biochemical 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 Physiological 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 functional improvement glucose metabolism glucose tolerance glucose uptake human study improved insulin secretion insulin sensitivity interest mRNA Expression new therapeutic target novel strategies obesity treatment oral glucose tolerance pharmacologic prevent randomized placebo controlled 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），从米拉贝隆的反应开始，它是一种 β3 肾上腺素受体 (β3AR) 激动剂，存在于脂肪细胞和平滑肌中，并且米拉贝隆是 FDA 批准用于人类治疗肥胖、胰岛素抵抗的药物。米拉贝隆持续诱导 SC WAT 开始 12 周，这导致口服葡萄糖的改善耐受性和较低的 HbA1c 改善葡萄糖稳态的机制涉及一个小因素。胰岛素敏感性的改善和 β 细胞功能（胰岛素分泌）的显着改善肌肉氧化型 1 纤维增加；然而，体重没有减轻，也没有棕色脂肪的产生。由于胰腺 β 细胞和肌肉不表达 β3AR，米拉贝隆在这些方面的有益作用细胞可能是通过间接机制发生的。米拉贝隆的生理作用可能部分是通过米色脂肪的诱导介导的，米色脂肪代表葡萄糖和脂质的代谢库，可能会改变脂肪重塑。脂肪组织和其他器官的变化可能会导致针对其他组织的副作用。具体目标 1. 为了检查 β3 激动剂米拉贝隆对葡萄糖代谢的影响，我们将全面分析糖尿病前期受试者的糖耐量、胰岛素敏感性和 β 细胞功能为期 4 个月的安慰剂对照随机试验我们将评估脂肪组织的变化，包括开始、我们还将全面描述脂肪细胞的炎症、纤维化和胰岛素刺激的葡萄糖摄取。通过 RNA-seq 在 SC WAT 中进行基因表达，以确定潜在的机制，例如改变的脂肪因子谱。具体目标 2. 我们勇敢地承认米拉贝隆会导致表达 β3AR 的细胞改变水平我们将使用生化和影响外周细胞类型（例如 β 细胞和肌肉）的分泌因子。确定米拉贝隆条件培养基处理机制的药理学方法脂肪细胞在体外增加肌肉中的 PGC1α 表达我们将利用公正的方法来识别。我们将观察脂肪细胞条件培养基中脂质、代谢物和外泌体 miRNA 组成的变化。使用这些方法通过米拉贝隆治疗来识别血浆中的分子，这些分子负责 β细胞和肌肉功能的改善。临床相关性：米拉贝隆治疗因改善而对糖耐量产生积极影响胰岛素敏感性和 β 细胞功能可用于预防糖尿病前期转化为糖尿病前期。糖尿病或用作糖尿病的治疗方法此应用也将增加我们对糖尿病的了解。米拉贝隆的作用机制可能揭示新的治疗靶点