Metabolic Effects of Melanocortin 4 Receptor Agonism

黑皮质素 4 受体激动剂的代谢效应

基本信息

批准号：
9549961
负责人：
Ranganath Muniyappa
金额：
$ 27.55万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9549961
关键词：
ART protein Acute Adult Adverse effects Agonist Animal Model Animals Blood Pressure Body Weight Body Weight decreased Carbohydrates Cardiovascular system Chronic Clinical Trials Colon Corticotropin Cross-Over Studies Data Desire for food Diet Dose Double-Blind Method Eating Endocrine Energy Metabolism Epithelial Etiology Exercise Exons Family Fasting Fatty acid glycerol esters Food Glucose Heart Rate Homeostasis Hormonal Hour Human Hypothalamic structure Infusion procedures Insulin Intestines L Cells Macaca mulatta Maintenance Measures Melanocortin 4 Receptor Melanocyte stimulating hormone Metabolic Mus Nucleotides Obesity Peptides Placebo Control Placebos Pro-Opiomelanocortin Production Proteins Randomized Randomized Controlled Trials Receptor Activation Regulation Rest Rodent Role Signal Transduction Sleep Standardization System Testing Therapeutic Agents Variant Weight Weight-Loss Drugs alpha-Melanocyte stimulating hormone glucagon-like peptide 1 glucose tolerance improved in vivo novel obesity treatment peptide hormone receptor reduced food intake relating to nervous system respiratory subcutaneous treatment duration trend weight maintenance

ART protein Acute Adult Adverse effects Agonist Animal Model Animals Blood Pressure Body Weight Body Weight decreased Carbohydrates Cardiovascular system Chronic Clinical Trials Colon Corticotropin Cross-Over Studies Data Desire for food Diet Dose Double-Blind Method Eating Endocrine Energy Metabolism Epithelial Etiology Exercise Exons Family Fasting Fatty acid glycerol esters Food Glucose Heart Rate Homeostasis Hormonal Hour Human Hypothalamic structure Infusion procedures Insulin Intestines L Cells Macaca mulatta Maintenance Measures Melanocortin 4 Receptor Melanocyte stimulating hormone Metabolic Mus Nucleotides Obesity Peptides Placebo Control Placebos Pro-Opiomelanocortin Production Proteins Randomized Randomized Controlled Trials Receptor Activation Regulation Rest Rodent Role Signal Transduction Sleep Standardization System Testing Therapeutic Agents Variant Weight Weight-Loss Drugs alpha-Melanocyte stimulating hormone glucagon-like peptide 1 glucose tolerance improved in vivo novel obesity treatment peptide hormone receptor reduced food intake relating to nervous system respiratory subcutaneous treatment duration trend weight maintenance

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项目摘要

In this randomized, double-blind, placebo-controlled, multiple-dose, 2-period, crossover study of 12 obese subjects, we examined the effect of RM-493 on resting energy expenditure in a room calorimeter. Twelve healthy adults (6 M, 6 F) with BMI 35.7 2.9 kg/m2 (mean, SD) received RM-493 (1 mg/24 h) or placebo by continuous subcutaneous infusion over 72 hours, followed immediately by crossover to the alternate treatment. All subjects received a weight-maintenance diet (50% carbohydrate, 30% fat, 20% protein) and performed 30 minutes of standardized exercise daily. Continuous EE was measured on the third treatment day in a room calorimeter and REE in the fasting state was defined as the mean of two 30-minute resting periods. RM-493 increased REE vs. placebo by 6.4% (95% CI: 0.68 to 13.02 %), on average by 111 kcal/24h (95% CI: 15 to 207 kcal, p=0.03). Total daily EE trended higher while the thermic effect of a test meal and exercise EE did not differ significantly. The 23-h non-exercise respiratory quotient was lower during RM-493 treatment (0.833 0.021 vs. 0.848 0.022, p=0.02). None of our subjects had exon nucleotide variants of MC4R associate with obesity. Recently, MC4R receptor activation in intestinal epithelial L-cells has been shown to acutely increase GLP-1 and PYY secretion in vivo in mice, and in colon explants from both mice and human. Similar to the rodent data, fasting total GLP-1 and PYY levels were slightly, but significantly increased during RM-493 administration in our study. Thus, it is possible that MC4R-induced GLP-1 production may contribute to eventual beneficial effects on insulin and glucose, while PYY (assumed to be PYY3-36) can positively impact energy metabolism during obesity treatment. It is possible that increases in both peptides may contribute to the weight loss effect of RM-493 seen in animals. No adverse effect on heart rate or blood pressure was observed.

在这项随机，双盲，安慰剂对照的，多剂量的，2周期的，对12名受试者的跨界研究，我们检查了RM-493对房间热量计中静息能量支出的影响。 BMI 35.7 2.9 kg/m2（平均，SD）的十二名健康成年人（6 m，6 f）通过连续72小时在72小时内连续下输注，然后立即交叉到替代处理。所有受试者接受了体重维护饮食（50％碳水化合物，30％脂肪，20％蛋白质），并每天进行30分钟的标准运动。连续EE是在第三天在室内量热计中测量的，而禁食状态的REE定义为两个30分钟的休息期的平均值。 RM-493将REE与安慰剂增加6.4％（95％CI：0.68至13.02％），平均增加111 kcal/24h（95％CI：15至207 kcal，p = 0.03）。每日总EE趋势更高，而测试餐和运动的热效应没有显着差异。在RM-493治疗期间，23-H非运动呼吸商较低（0.833 0.021 vs. 0.848 0.022，p = 0.02）。我们的受试者都没有MC4R的外显子核苷酸变体与肥胖相关。最近，已经证明，肠上皮L细胞中的MC4R受体激活可急剧增加小鼠体内的GLP-1和PYY分泌，以及来自小鼠和人类的结肠外植体。与啮齿动物的数据相似，禁食总GLP-1和PYY水平略有略有，但在我们的研究中，在RM-493给药期间显着增加。因此，MC4R诱导的GLP-1产生可能会导致对胰岛素和葡萄糖的最终有益作用，而PYY（假定为PYY3-36）可能会对肥胖症治疗期间的能量代谢产生积极影响。两种肽的增加可能会导致动物中看到的RM-493的减肥效应。没有观察到心率或血压的不良影响。