Metabolic Effects of Melanocortin 4 Receptor Agonism

黑皮质素 4 受体激动剂的代谢效应

• 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
• 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

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.

在这项对 12 名肥胖受试者进行的随机、双盲、安慰剂对照、多剂量、2 个周期的交叉研究中，我们在室内热量计中检查了 RM-493 对静息能量消耗的影响。 12 名 BMI 35.7±2.9 kg/m2（平均值，SD）的健康成人（6 M，6 F）通过连续皮下输注超过 72 小时接受 RM-493（1 mg/24 小时）或安慰剂，然后立即交叉至替代方案治疗。 所有受试者均接受体重维持饮食（50% 碳水化合物、30% 脂肪、20% 蛋白质），并每天进行 30 分钟的标准化锻炼。 在治疗第三天在室内热量计中测量连续 EE，并将禁食状态下的 REE 定义为两个 30 分钟休息时间的平均值。 与安慰剂相比，RM-493 使 REE 增加 6.4%（95% CI：0.68 至 13.02 %），平均增加 111 kcal/24 小时（95% CI：15 至 207 kcal，p=0.03）。 每日总能量效率呈上升趋势，而测试餐和运动能量效率的热效应没有显着差异。 RM-493 治疗期间 23 小时非运动呼吸商较低（0.833 0.021 vs. 0.848 0.022，p=0.02）。 我们的受试者都没有与肥胖相关的 MC4R 外显子核苷酸变异。 最近，肠上皮 L 细胞中 MC4R 受体的激活已被证明可急剧增加小鼠体内以及小鼠和人类结肠外植体中 GLP-1 和 PYY 的分泌。 与啮齿动物数据类似，在我们的研究中，空腹总 GLP-1 和 PYY 水平略有上升，但在 RM-493 给药期间显着增加。 因此，MC4R 诱导的 GLP-1 产生可能有助于最终对胰岛素和葡萄糖产生有益作用，而 PYY（假设为 PYY3-36）可以在肥胖治疗期间对能量代谢产生积极影响。这两种肽的增加可能有助于 RM-493 在动物身上看到的减肥效果。 没有观察到对心率或血压的不利影响。