Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
Diabetes Obes Metab. 2010 Jun;12(6):532-9. doi: 10.1111/j.1463-1326.2009.01189.x.
We have recently shown that intranasal administration of mouse [d-Leu-4]-OB3 reconstituted in Intravail to male Swiss Webster mice resulted in significantly higher bioavailability than commonly used injections methods of delivery. The absorption profile associated with intranasal delivery of mouse [d-Leu-4]-OB3 showed an early peak representing absorption across the nasal mucosa, and a later peak suggesting a gastrointestinal site of uptake.
In the present study, we examined the effects of orally administered (by gavage) mouse [d-Leu-4]-OB3 on energy balance, glycaemic control and serum osteocalcin levels in male C57BL/6J wild-type and ob/ob mice allowed food and water ad libitum or calorie restricted by 40% of normal intake.
In wild-type mice fed ad libitum, oral delivery of mouse [d-Leu-4]-OB3 reduced body weight gain, food intake and serum glucose, by 4.4, 6.8 and 28.2% respectively. Serum osteocalcin levels and water intake were essentially the same in control and treated wild-type mice. In ob/ob mice fed ad libitum, mouse [d-Leu-4]-OB3 reduced body weight gain, food intake, water intake and serum glucose by 11.6, 16.5, 22.4 and 24.4% respectively. Serum osteocalcin in ob/ob mice treated with mouse [d-Leu-4]-OB3 was elevated by 62% over controls. Calorie restriction alone caused significant weight loss in both wild-type (9.0%) and ob/ob (4.8%) mice, and mouse [d-Leu-4]-OB3 did not further enhance this weight loss. As expected, serum glucose levels in wild-type and ob/ob mice were significantly reduced by calorie restriction alone. Mouse [d-Leu-4]-OB3 further reduced serum glucose in wild-type mice and normalized levels in ob/ob mice. Calorie restriction alone reduced serum osteocalcin levels by 44.2% in wild-type mice and by 19.1% in ob/ob mice. Mouse [d-Leu-4]-OB3 prevented this decrease in groups of mice.
The results of this study suggest that oral delivery of mouse [d-Leu-4]-OB3 in Intravail is possible and may have potential not only as an alternative therapy in the treatment of human obesity and some of its associated metabolic dysfunctions, but also may help to prevent and/or reverse at least some of the bone loss which accompanies osteoporosis, anorexia nervosa and other wasting diseases.
我们最近发现，在 Intravail 中重新配制的鼻腔内给予雄性瑞士 Webster 小鼠的[D-Leu-4]-OB3 与常用的注射给药方法相比，其生物利用度显著提高。鼻腔给予[D-Leu-4]-OB3 后的吸收曲线显示出一个早期峰值，代表鼻黏膜的吸收，一个后期峰值提示胃肠道吸收部位。
在本研究中，我们研究了口服（灌胃）给予雄性 C57BL/6J 野生型和 ob/ob 小鼠[D-Leu-4]-OB3 对能量平衡、血糖控制和血清骨钙素水平的影响，这些小鼠可以自由摄入食物和水或通过减少 40%的正常摄入量来限制热量摄入。
在自由进食的野生型小鼠中，口服给予[D-Leu-4]-OB3 分别使体重增加、食物摄入和血清葡萄糖减少 4.4%、6.8%和 28.2%。对照和治疗的野生型小鼠的血清骨钙素水平和水摄入量基本相同。在自由进食的 ob/ob 小鼠中，[D-Leu-4]-OB3 使体重增加、食物摄入、水摄入和血清葡萄糖分别减少 11.6%、16.5%、22.4%和 24.4%。ob/ob 小鼠给予[D-Leu-4]-OB3 后，血清骨钙素水平升高 62%。单独的热量限制使野生型（9.0%）和 ob/ob（4.8%）小鼠体重显著减轻，[D-Leu-4]-OB3 并未进一步增强这种体重减轻。如预期的那样，单独的热量限制使野生型和 ob/ob 小鼠的血清葡萄糖水平显著降低。[D-Leu-4]-OB3 进一步降低了野生型小鼠的血清葡萄糖水平，并使 ob/ob 小鼠的水平正常化。单独的热量限制使野生型小鼠的血清骨钙素水平降低 44.2%，ob/ob 小鼠降低 19.1%。[D-Leu-4]-OB3 阻止了这些小鼠组中骨钙素水平的下降。
本研究结果表明，鼻腔内给予[D-Leu-4]-OB3 是可能的，并且不仅可能作为治疗人类肥胖及其相关代谢功能障碍的一种替代疗法，而且可能有助于预防和/或逆转骨质疏松症、神经性厌食症和其他消耗性疾病伴随的至少部分骨丢失。
