Obesity and Liver Pharmacology, Integrated Physiology Research, Novo Nordisk A/S, Bagsværd, Denmark.
Liver and Gut Biology, Obesity & NASH, Global Drug Discovery, Novo Nordisk A/S, Bagsværd, Denmark.
Cell Rep. 2024 Aug 27;43(8):114501. doi: 10.1016/j.celrep.2024.114501. Epub 2024 Jul 25.
Evaluation of weight loss drugs is usually performed in diet-induced obese mice housed at ∼22°C. This is a cold stress that increases energy expenditure by ∼35% compared to thermoneutrality (∼30°C), which may overestimate drug-induced weight loss. We investigated five anti-obesity mechanisms that have been in clinical development, comparing weight loss in mice housed at 22°C vs. 30°C. Glucagon-like peptide-1 (GLP-1), human fibroblast growth factor 21 (hFGF21), and melanocortin-4 receptor (MC4R) agonist induced similar weight losses. Peptide YY elicited greater vehicle-subtracted weight loss at 30°C (7.2% vs. 1.4%), whereas growth differentiation factor 15 (GDF15) was more effective at 22°C (13% vs. 6%). Independent of ambient temperature, GLP-1 and hFGF21 prevented the reduction in metabolic rate caused by weight loss. There was no simple rule for a better prediction of human drug efficacy based on ambient temperature, but since humans live at thermoneutrality, drug testing using mice should include experiments near thermoneutrality.
体重减轻药物的评估通常在环境温度约为 22°C 的饮食诱导肥胖小鼠中进行。这是一种冷应激，与热中性（约 30°C）相比，能量消耗增加约 35%，这可能会高估药物引起的体重减轻。我们研究了五种处于临床开发阶段的抗肥胖机制，比较了在 22°C 和 30°C 下饲养的小鼠的体重减轻情况。胰高血糖素样肽 1（GLP-1）、人成纤维细胞生长因子 21（hFGF21）和黑素皮质素 4 受体（MC4R）激动剂引起的体重减轻相似。肽 YY 在 30°C 时引起更大的载体 subtracted 体重减轻（7.2% vs. 1.4%），而生长分化因子 15（GDF15）在 22°C 时更有效（13% vs. 6%）。独立于环境温度，GLP-1 和 hFGF21 可防止因体重减轻引起的代谢率降低。基于环境温度预测人类药物疗效没有简单的规则，但由于人类生活在热中性状态下，使用小鼠进行药物测试应包括接近热中性的实验。
