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Background:We have recently shown that intranasal administration of mouse ]-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. Aim and Methods: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. Results: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. Conclusions: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.

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