Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark.
Nordic Bioscience Biomarkers and Research, Department of Endocrinology, Herlev, Denmark
J Pharmacol Exp Ther. 2020 May;373(2):269-278. doi: 10.1124/jpet.119.263400. Epub 2020 Feb 18.
Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of type 2 diabetes and obesity because of their beneficial effects on body weight, blood glucose, insulin sensitivity, and food preference, at least short-term. DACRAs activate the receptors for a prolonged time period, resulting in metabolic effects superior to those of amylin. Because of the prolonged receptor activation, different dosing intervals and, hence, less frequent receptor activation might change the efficacy of DACRA treatment in terms of weight loss and food preference. In this study, we compared daily dosing to dosing every other day with the aim of understanding the optimal balance between efficacy and tolerability. Obese and lean male Sprague-Dawley rats were treated with the DACRA KBP-088, applying two different dosing intervals (1.5 nmol/kg once daily and 3 nmol/kg every other day) to assess the effect on body weight, food intake, glucose tolerance, and food preference when given the choice between chow (13% fat) and a high-fat diet (60% fat). Treatment with KBP-088 induced significant weight loss, reduction in adiposity, improvement in glucose control, and altered food preference toward food that is less calorie-dense. KBP-088 dosed every other day (3 nmol/kg) was superior to KBP-088 once daily (1.5 nmol/kg) in terms of weight loss and improvement of food preference. The beneficial effects were evident in both lean and obese rats. Hence, dosing KBP-088 every other day positively affects overall efficacy on metabolic parameters regardless of the lean/obese state, suggesting that less-frequent dosing with KBP-088 could be feasible. SIGNIFICANCE STATEMENT: Here, we show that food preference can be altered chronically toward choices that are less calorie-dense by pharmacological treatment. Further, pharmacological dosing regimens affect the efficacy differently, as dosing every other day improved body weight loss and alterations in food preference compared with daily dosing. This suggest that alterations of the dosing regimens could be feasible in the treatment of obesity.
双重淀粉样肽-1 和降钙素受体激动剂（DACRAs）因其对体重、血糖、胰岛素敏感性和食物偏好的有益影响，至少在短期内在 2 型糖尿病和肥胖症的治疗中成为有希望的候选药物。DACRAs 会在很长一段时间内激活受体，从而产生优于淀粉样肽的代谢作用。由于受体激活时间延长，不同的给药间隔时间，因此受体激活频率降低，可能会改变 DACRA 治疗在减轻体重和改变食物偏好方面的疗效。在这项研究中，我们比较了每日给药和隔日给药的效果，目的是了解在疗效和耐受性之间取得最佳平衡的方法。肥胖和瘦的雄性 Sprague-Dawley 大鼠接受 DACRA KBP-088 治疗，应用两种不同的给药间隔（每天 1.5 nmol/kg 和隔日 3 nmol/kg），以评估在给予选择食用标准饮食（13%脂肪）和高脂肪饮食（60%脂肪）之间时对体重、食物摄入量、葡萄糖耐量和食物偏好的影响。KBP-088 治疗可显著减轻体重、减少脂肪堆积、改善葡萄糖控制并改变对热量密度较低的食物的偏好。隔日给药（3 nmol/kg）优于每日一次给药（1.5 nmol/kg），可显著减轻体重和改善食物偏好。这些有益作用在瘦型和肥胖型大鼠中均有体现。因此，无论肥胖或瘦型，隔日给予 KBP-088 可对代谢参数的整体疗效产生积极影响，这表明 KBP-088 较少的给药频率可能是可行的。意义：在这里，我们表明通过药物治疗可以长期改变食物偏好，使其倾向于选择热量密度较低的食物。此外，药物给药方案会以不同的方式影响疗效，因为与每日给药相比，隔日给药可改善体重减轻和食物偏好的改变。这表明改变给药方案在肥胖症的治疗中是可行的。
