Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
J Clin Endocrinol Metab. 2023 Aug 18;108(9):2262-2271. doi: 10.1210/clinem/dgad139.
Individual responses to weight loss (WL) medications vary widely and prediction of response remains elusive.
We investigated biomarkers associated with use of lorcaserin (LOR), a 5HT2cR agonist that targets proopiomelanocortin (POMC) neurons that regulate energy and glucose homeostasis, to identify predictors of clinical efficacy.
Thirty individuals with obesity were treated with 7 days of placebo and LOR in a randomized crossover study. Nineteen participants continued on LOR for 6 months. Cerebrospinal fluid (CSF) POMC peptide measurements were used to identify potential biomarkers that predict WL. Insulin, leptin, and food intake during a meal were also studied.
LOR induced a significant decrease in CSF levels of the POMC prohormone and an increase in its processed peptide β-endorphin after 7 days; β-endorphin/POMC increased by 30% (P < .001). This was accompanied by a substantial decrease in insulin, glucose, and homeostasis model assessment of insulin resistance before WL. Changes in CSF POMC peptides persisted after WL (6.9%) at 6 months that were distinct from prior reports after diet alone. Changes in POMC, food intake, or other hormones did not predict WL. However, baseline CSF POMC correlated negatively with WL (P = .07) and a cutoff level of CSF POMC was identified that predicted more than 10% WL.
Our results provide evidence that LOR affects the brain melanocortin system in humans and that effectiveness is increased in individuals with lower melanocortin activity. Furthermore, early changes in CSF POMC parallel WL-independent improvements in glycemic indexes. Thus, assessment of melanocortin activity could provide a way to personalize pharmacotherapy of obesity with 5HT2cR agonists.
个体对减肥药物的反应差异很大，反应预测仍然难以捉摸。
我们研究了与 lorcaserin（LOR）使用相关的生物标志物，LOR 是一种 5HT2cR 激动剂，靶向调节能量和葡萄糖稳态的 proopiomelanocortin（POMC）神经元，以确定临床疗效的预测因子。
30 名肥胖患者在随机交叉研究中接受了 7 天安慰剂和 LOR 治疗。19 名参与者继续接受 LOR 治疗 6 个月。使用脑脊液（CSF）POMC 肽测量来识别潜在的生物标志物，预测减肥效果。还研究了胰岛素、瘦素和进餐时的食物摄入量。
LOR 在 7 天后诱导 CSF 中 POMC 前激素水平显著降低，并使其加工肽β-内啡肽增加 30%（P<0.001）。这伴随着减肥前胰岛素、葡萄糖和稳态模型评估的胰岛素抵抗显著降低。在 6 个月时（6.9%），减肥后的 CSF POMC 肽变化持续存在，与单独饮食后的先前报告不同。CSF POMC 的变化与减肥无关（P=0.07），并且确定了 CSF POMC 的截断水平，该水平预测超过 10%的减肥。
我们的结果提供了证据表明 LOR 会影响人类的脑黑皮质素系统，并且在黑皮质素活性较低的个体中，其有效性会增加。此外，CSF POMC 的早期变化与血糖指数的减肥独立改善平行。因此，黑皮质素活性的评估可以为使用 5HT2cR 激动剂对肥胖进行个体化药物治疗提供一种方法。
