Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys
Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys
复制标题
DOI：
10.1152/ajpendo.00089.2006
复制
发表时间：
2007-03-01
影响因子：
5.1
通讯作者：
Kussie, Paul
中科院分区：
文献类型：
--
作者：
Sun, Haijun D.;Malabunga, Maria;Kussie, Paul
我们制备了三种针对成纤维细胞生长因子受体-1(FGFR1)的全人单抗拮抗剂，它们可以有效地阻断成纤维细胞生长因子信号转导。我们发现，针对受体的c-剪接形式(FGFR1c)的抗体在给小鼠每周三次腹腔注射时出现厌食症，导致快速、剂量依赖性的体重下降，在2周内稳定在35-40%(剂量为4 mg/kg)。动物在治疗期间看起来很健康，在清除了血液中的抗体后，恢复了正常的体重和生长轨迹。对食物消耗和能量消耗的测量表明，体重的快速下降主要是由于能量摄入的减少，而不是能量消耗的增加或恶病质，并伴随着比瘦体重更大的脂肪减少。大鼠缺乏条件性味觉厌恶、异食癖行为和需要诱导的盐摄入量减少，表明低食症不是由于身体不适或疾病引起的。为了支持下丘脑的作用部位，我们发现，在腹腔注射后，抗FGFR1c(IMC-A1)，而不是对照抗体，积聚在正中隆起和邻近的内侧基底下丘脑，FGFR1c在小鼠的下丘脑中丰富。此外，通过第三脑室单次脑室注射IMC-A1 3mgIMC-A1可使小鼠摄食量减少36%，在随后的24小时内体重减轻6%。我们的数据表明，通过FGFR1c传递的成纤维细胞生长因子信号可能在下丘脑的摄食回路中发挥生理作用，阻断它会导致吞噬减少和体重减轻。
We generated three fully human monoclonal antibody antagonists against fibroblast growth factor receptor-1 (FGFR1) that potently block FGF signaling. We found that antibodies targeting the c-splice form of the receptor (FGFR1c) were anorexigenic when administered intraperitoneally three times weekly to mice, resulting in rapid, dose-dependent weight loss that plateaued (for doses > 4 mg/kg) at 35-40% in 2 wk. Animals appeared healthy during treatment and regained their normal body weights and growth trajectories upon clearance of the antibodies from the bloodstream. Measurements of food consumption and energy expenditure indicated that the rapid weight loss was induced primarily by decreased energy intake and not by increased energy expenditure or cachexia and was accompanied by a greater reduction in fat than lean body mass. Hypophagia was not caused through malaise or illness, as indicated by absence of conditioned taste aversion, pica behavior, and decreased need-induced salt intake in rats. In support of a hypothalamic site of action, we found that, after intraperitoneal injections, anti-FGFR1c (IMC-A1), but not a control antibody, accumulated in the median eminence and adjacent mediobasal hypothalamus and that FGFR1c is enriched in the hypothalamus of mice. Furthermore, a single intracerebroventricular administration of 3 mu g of IMC-A1 via the 3rd ventricle to mice caused an similar to 36% reduction in food intake and an similar to 6% weight loss within the ensuing 24 h. Our data suggest that FGF signaling through FGFR1c may play a physiological role in hypothalamic feeding circuit and that blocking it leads to hypophagia and weight loss.