Endothelin-1 in Obesity and Insulin Resistance

内皮素 1 在肥胖和胰岛素抵抗中的作用

基本信息

批准号：
10211313
负责人：
Joshua S Speed
金额：
$ 40.77万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-09 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211313
关键词：
Address Adipocytes Adipose tissue Affect Agonist American Attenuated Blood Glucose Cardiovascular Diseases Cardiovascular system Clinical Data Diabetes Mellitus Endothelial Cells Endothelin A Receptor Endothelin-1 Fasting Fatty acid glycerol esters Glucose Glucose Intolerance HIF1A gene Health High Fat Diet Human Hypothalamic structure Hypoxia Impairment In Vitro Incidence Individual Insulin Insulin Resistance Knock-out Knockout Mice Laboratories Lipids Lipolysis Liver LoxP-flanked allele Mediating Messenger RNA Metabolic Diseases Metabolic syndrome Modeling Morbid Obesity Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Outcome PPAR gamma Patients Peptides Peripheral Pharmacology Physiological Plasma Population Prevalence Production Receptor Activation Receptor Inhibition Risk Factors Rodent Rodent Model Scheme Signal Pathway Sleep Apnea Syndromes System Techniques Testing Thinness Tissues Transgenic Mice Triglycerides Visceral adiponectin blood glucose regulation bosentan cardiovascular risk factor diet-induced obesity feeding gain of function glucose metabolism glucose tolerance glucose uptake hypoxia inducible factor 1 impaired glucose tolerance improved in vivo inhibitor/antagonist insulin sensitivity insulin signaling insulin tolerance leptin receptor lipid metabolism mouse model novel obese patients overexpression pre-clinical receptor response western diet

项目摘要

Project Summary Insulin resistance (IR) is a major health problem in the U.S. It precludes type II diabetes and is often present in patients suffering from obesity, both being major risk factors for cardiovascular disease. Currently, mechanisms leading to IR are not fully understood. ET-1 is a vasoactive peptide primarily released by endothelial cells. It is increased in patients with obesity and associated with IR. ET-1 is elevated in response to hypoxia, which occurs in individuals with obesity. It activates two receptors, ETA and ETB, which typically oppose each other physiologically. Our preliminary data indicate that inhibiting ETB receptors in rodents, either genetically or pharmacologically, improves insulin tolerance and reduces fasting blood glucose. This improvement in glucose control is associated with an increase in plasma adiponectin and adipose adiponectin and peroxisome proliferator-activated receptor gamma (PPAR-γ) mRNA. In addition, adipocyte specific ETB gain of function mice have exacerbated glucose intolerance in response to high fat feeding, while adipocyte ETB knockout mice have improved glucose and insulin tolerance compared to floxed control littermates. These data suggest the adipose tissue as a possible target for ET-1 induced reduction in insulin signaling. It has been previously shown that activation of ETB receptors on cultured adipocytes inhibits the anti-lipolytic effects of insulin. Furthermore, blockade of ETB receptors improves insulin sensitivity in a rodent model of sleep apnea. These data suggest that increased ET-1 observed in patients with obesity may promote IR via the ETB receptor. Thus, we hypothesize that that obesity induced tissue hypoxia promotes ET-1/ETB receptor activation in adipose leading to IR on adipocytes, PPAR-γ inhibition and reduced Adiponectin release by adipocytes thereby causing IR in muscle and liver tissue. To test this hypothesis, we will utilize both in vivo and in vitro techniques. First, using cultured adipocytes, we will determine whether activation of ETB receptors inhibits PPAR-γ, reduces adiponectin secretion, and causes insulin resistance on adipocytes. Next, we will used clinically approved inhibitors of ET-1 receptors in a model of diet induced obesity and IR, and we will utilize two novel mouse models that were produced by our lab that allow us to over-express or knockout the ETB. To test this hypothesis, the following specific aims will be tested: Specific aim 1: To test the hypothesis that ETB receptor activation directly inhibits insulin signaling on adipocytes and reduces adiponectin production by inhibiting PPAR-γ. Specific aim 2: To test the hypothesis that ETB receptor activation on adipocytes promotes insulin resistance by inhibiting PPAR-γ and reducing adiponectin release in mice. Specific aim 3: To test the hypothesis that ETB receptor blockade increases plasma adiponectin and improves insulin resistance in obese mice.

项目概要胰岛素抵抗 (IR) 是美国的一个主要健康问题。它可以预防 II 型糖尿病，并且经常出现在患有肥胖症的患者，两者都是目前心血管疾病的主要危险因素。导致 IR 的机制尚不完全清楚 ET-1 是一种主要通过释放的血管活性肽。内皮细胞在肥胖患者中增加，并且与 IR 相关。缺氧，发生在肥胖个体中，它会激活两种受体：ETA 和 ETB，这通常是两种受体。我们的初步数据表明，抑制啮齿类动物的 ETB 受体。从遗传或药理学角度来说，可以改善胰岛素耐受性并降低空腹血糖。血糖控制的改善与血浆脂联素和脂肪脂联素的增加有关和过氧化物酶体增殖物激活受体γ (PPAR-γ) mRNA 此外，脂肪细胞特异性ETB。功能获得小鼠因高脂肪喂养而加剧了葡萄糖不耐受，而脂肪细胞与 floxed 对照同窝小鼠相比，ETB 敲除小鼠的葡萄糖和胰岛素耐受性有所改善。数据表明，脂肪组织可能是 ET-1 诱导胰岛素信号传导减少的靶标。先前表明，培养脂肪细胞上 ETB 受体的激活会抑制此外，阻断 ETB 受体可改善睡眠呼吸暂停啮齿动物模型中的胰岛素敏感性。这些数据表明，在肥胖患者中观察到的 ET-1 增加可能通过 ETB 促进 IR 因此，我们追寻肥胖引起的组织缺氧促进ET-1/ETB受体。脂肪激活导致脂肪细胞 IR、PPAR-γ 抑制和脂联素释放减少脂肪细胞导致肌肉和肝脏组织中的 IR。为了检验这一假设，我们将利用两者。首先，使用培养的脂肪细胞，我们将确定ETB是否被激活。受体抑制 PPAR-γ，减少脂联素分泌，引起脂肪细胞胰岛素抵抗。我们将在饮食诱发的肥胖和 IR 模型中使用临床批准的 ET-1 受体抑制剂，并且我们将利用我们实验室生产的两种新型小鼠模型，使我们能够过度表达或敲除为了检验这一假设，将检验以下具体目标：具体目标 1：检验 ETB 受体激活直接抑制胰岛素信号传导的假设脂肪细胞并通过抑制 PPAR-γ 减少脂联素的产生。具体目标 2：检验脂肪细胞上 ETB 受体激活促进胰岛素抵抗的假设通过抑制 PPAR-γ 并减少小鼠脂联素释放。具体目标 3：检验 ETB 受体阻断增加血浆脂联素并改善的假设肥胖小鼠的胰岛素抵抗。