CNS Pharmacology Neurobiology, Actelion Pharmaceuticals Ltd. Allschwil, Switzerland.
Immunology, Actelion Pharmaceuticals Ltd. Allschwil, Switzerland.
Front Pharmacol. 2013 Dec 30;4:165. doi: 10.3389/fphar.2013.00165. eCollection 2013.
The orexin system regulates feeding, nutrient metabolism and energy homeostasis. Acute pharmacological blockade of orexin receptor 1 (OXR-1) in rodents induces satiety and reduces normal and palatable food intake. Genetic OXR-1 deletion in mice improves hyperglycemia under high-fat (HF) diet conditions. Here we investigated the effects of chronic treatment with the novel selective OXR-1 antagonist ACT-335827 in a rat model of diet-induced obesity (DIO) associated with metabolic syndrome (MetS). Rats were fed either standard chow (SC) or a cafeteria (CAF) diet comprised of intermittent human snacks and a constant free choice between a HF/sweet (HF/S) diet and SC for 13 weeks. Thereafter the SC group was treated with vehicle (for 4 weeks) and the CAF group was divided into a vehicle and an ACT-335827 treatment group. Energy and water intake, food preference, and indicators of MetS (abdominal obesity, glucose homeostasis, plasma lipids, and blood pressure) were monitored. Hippocampus-dependent memory, which can be impaired by DIO, was assessed. CAF diet fed rats treated with ACT-335827 consumed less of the HF/S diet and more of the SC, but did not change their snack or total kcal intake compared to vehicle-treated rats. ACT-335827 increased water intake and the high-density lipoprotein associated cholesterol proportion of total circulating cholesterol. ACT-335827 slightly increased body weight gain (4% vs. controls) and feed efficiency in the absence of hyperphagia. These effects were not associated with significant changes in the elevated fasting glucose and triglyceride (TG) plasma levels, glucose intolerance, elevated blood pressure, and adiposity due to CAF diet consumption. Neither CAF diet consumption alone nor ACT-335827 affected memory. In conclusion, the main metabolic characteristics associated with DIO and MetS in rats remained unaffected by chronic ACT-335827 treatment, suggesting that pharmacological OXR-1 blockade has minimal impact in this model.
食欲素系统调节进食、营养代谢和能量平衡。在啮齿动物中，急性药理学阻断食欲素受体 1（OXR-1）可诱导饱腹感，并减少正常和美味食物的摄入。在高脂肪（HF）饮食条件下，小鼠的 OXR-1 基因缺失可改善高血糖。在这里，我们研究了新型选择性 OXR-1 拮抗剂 ACT-335827 在与代谢综合征（MetS）相关的饮食诱导肥胖（DIO）大鼠模型中的慢性治疗作用。大鼠喂食标准饲料（SC）或自助餐（CAF）饮食，由间歇性人类零食和 HF/甜食（HF/S）饮食和 SC 之间的自由选择组成，共 13 周。此后，SC 组给予载体（4 周），CAF 组分为载体和 ACT-335827 治疗组。监测能量和水摄入、食物偏好以及 MetS 指标（腹部肥胖、葡萄糖稳态、血浆脂质和血压）。评估了可能被 DIO 损害的海马依赖记忆。与载体治疗的大鼠相比，用 ACT-335827 治疗的 CAF 饮食喂养的大鼠消耗的 HF/S 饮食较少，而消耗的 SC 较多，但它们的零食或总卡路里摄入量没有变化。ACT-335827 增加了水摄入量和高密度脂蛋白相关胆固醇在总循环胆固醇中的比例。ACT-335827 略微增加了体重增加（与对照组相比增加 4%）和饲料效率，而没有引起食欲亢进。这些作用与 CAF 饮食摄入引起的空腹血糖和甘油三酯（TG）血浆水平升高、葡萄糖不耐受、血压升高和肥胖症没有显著变化无关。CAF 饮食的单独摄入或 ACT-335827 均不影响记忆。总之，与大鼠 DIO 和 MetS 相关的主要代谢特征不受慢性 ACT-335827 治疗的影响，这表明在该模型中，药物 OXR-1 阻断的影响很小。
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