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

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

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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脂肪组织（SC WAT），以响应Mirabegron， β3肾上腺素受体（β3AR）激动剂。 β3AR在脂肪细胞和平滑肌中发现，以及 Mirabegron是FDA批准过度活跃膀胱的药物。治疗肥胖的胰岛素抵抗人米拉贝隆（Mirabegron）十二周始终诱导SC WAT成为，这导致了改善的口服葡萄糖耐受性和较低的HBA1C。改善葡萄糖体内稳态的机制涉及两者胰岛素敏感性的提高和β细胞功能（胰岛素分泌）的显着改善以及肌肉氧化1型纤维的增加；但是，没有体重减轻或诱导棕色脂肪。由于胰腺β细胞和肌肉不表达β3AR，因此米拉贝隆在这些中的有益作用细胞可能是通过间接机制发生的。 Mirabegron的物理作用可能部分是通过诱导米色脂肪的部分介导的，代表用于葡萄糖和脂质的代谢水槽，可能会改变脂肪重塑。另外，脂肪组织和其他器官的变化可能会导致靶向其他组织的次要作用。特定目的1。要检查β3激动剂米拉贝隆对葡萄糖代谢的影响，我们将在A 4个月，安慰剂对照，随机试验。我们将评估脂肪组织的变化，包括成为脂肪细胞炎症，纤维化和胰岛素刺激的葡萄糖摄取。我们还将完全描述通过RNA-Seq在SC WAT中的基因表达，以鉴定诸如脂肪因子谱改变的潜在机制。具体目标2。我们假设米拉贝隆会导致表达β3AR的细胞改变水平影响周围细胞类型的分泌因子，例如β细胞和肌肉。我们将使用生化和药理方法来识别米拉布隆处理的条件培养基的机制脂肪细胞在体外增加了肌肉中的PGC1α表达。我们将利用公正的方法来识别脂肪细胞条件培养基中脂质，代谢产物和外泌体miRNA组成的变化。我们将使用这些方法来鉴定通过米拉贝格隆治疗改变血浆中改变的分子，这些分子负责 β细胞和肌肉功能的改善。临床相关性：米拉贝隆治疗对改善葡萄糖耐受性具有积极影响在胰岛素敏感性和β细胞功能中。这可能是利用的，以防止将糖尿病转化为糖尿病或用作糖尿病患者的疗法。该应用程序还将增加我们对 Mirabegron作用的机制可能揭示了新的治疗靶标