Oral delivery of mouse [d‐Leu‐4]‐OB3, a synthetic peptide amide with leptin‐like activity, in male C57BL/6J wild‐type and ob/ob mice: effects on energy balance, glycaemic control and serum osteocalcin levels

Abstract

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.

Intranasal delivery of mouse [D‐Leu‐4]‐OB3, a synthetic peptide amide with leptin‐like activity, improves energy balance, glycaemic control, insulin sensitivity and bone formation in leptin‐resistant C57BLK/6‐m db/db mice

“…In this study, we have shown that the biological activity of mouse [D‐Leu‐4]‐OB3 is retained in leptin‐resistant C57BLK/6‐m db/db mice when it is delivered by intranasal instillation in Intravail ® . We recently reported similar results after oral administration of mouse [D‐Leu‐4]‐OB3 in Intravail ® to C57BL/6J leptin‐deficient ob/ob mice [6]. The pharmacokinetics of both intranasal [17] and oral [20] uptake of mouse [D‐Leu‐4]‐OB3 in Intravail ® have been previously described.…”

“…We and others have shown that ob/ob mice have reduced bone mass, mineralization, bone formation rate and lower serum levels of osteocalciin than their nonobese counterparts of the same age and sex [6,24]. Leptin, given by i.p.…”

“…injection to ob/ob mice, prevents this bone loss [24]. More recently, we reported that oral delivery of mouse [D‐Leu‐4]‐OB3 in Intravail ® also elevates serum levels of osteocalcin in ob/ob mice to even higher concentrations than those seen in wild‐type control mice [6]. Similar enhancement of serum osteocalcin was observed in this study following intranasal delivery of mouse [D‐Leu‐4]‐OB3 to leptin‐resistant db/db mice.…”

“…Reports from our laboratory [1][2][3][4][5][6], and a growing number of other laboratories [7][8][9][10][11][12][13][14][15][16], have consistently shown that the entire leptin molecule is not required for the expression of its biological activity. Utilizing in vitro and in vivo approaches, peripheral and intracerebroventricular delivery systems, a variety of physiological endpoints, and different animal models, these studies provide convincing evidence that synthetic peptide analogs that encompass the functional epitope of leptin contain sufficient information to influence leptin-modulated physiologies by pathways that complement, augment or diverge from those of endogenous leptin.…”

Brain Signaling Systems in the Type 2 Diabetes and Metabolic Syndrome: Promising Target to Treat and Prevent These Diseases

“…In C57BL/6J ob / ob mice this peptide improved the glucose control and insulin sensitivity [198]. On the basis of peptide [D-Leu-4]-OB-3, the drugs effective in intranasal and oral administration were developed whose activity significantly surpassed that of the same peptide when administered parenterally [199,200]. The peptide analogs of leptin easily penetrated the BBB and specifically interacted with leptin receptors in the CNS, activating leptin signaling in the hypothalamus [185].…”