Subcutaneous oxyntomodulin analogue administration reduces body weight in lean and obese rodents

• Published in: International Journal of Obesity Vol. 34; no. 12; pp. 1715 - 1725
• Main Authors: Liu, Y.L, Ford, H.E, Druce, M.R, Minnion, J.S, Field, B.C.T, Shillito, J.C, Baxter, J, Murphy, K.G, Ghatei, M.A, Bloom, S.R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2010; Nature Publishing Group
• Subjects: 631/443/319/1488; 692/308/409; 692/699/1702/393; 692/700/565/238; Adenosine; Adenylic acid; Animals; Anti-Obesity Agents - pharmacology; Biological and medical sciences; Body weight; Body Weight - drug effects; Body Weight - physiology; Cardiovascular diseases; Care and treatment; Complications and side effects; Diet; Eating - drug effects; Energy balance; Energy Metabolism - drug effects; Epidemiology; Food; Gastrointestinal Hormones - pharmacology; Gastrointestinal surgery; Glucagon; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide-1 Receptor; Health aspects; Health Promotion and Disease Prevention; Hospitals; Injections, Subcutaneous; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred C57BL; Obesity; original-article; Oxygen consumption; Oxyntomodulin; Patient outcomes; Peptide Hormones - pharmacology; Peptides; Physiological aspects; Public Health; Rats; Rats, Wistar; Receptors, Glucagon - drug effects; Research design; Risk factors; Rodents; Type 2 diabetes; Weight control; Weight Loss - drug effects; Weight Loss - physiology; United Kingdom; United Kingdom > UK; body weight; oxyntomodulin analogue; energy expenditure; food intake; Obesity; Nutrition; Body weight; Nutrition disorder; Weight loss; Rodentia; Metabolic diseases; Corporal biometry; Oxyntomodulin; Vertebrata; Mammalia; Gastrointestinal hormone; Food intake; Energetic cost; Analog; Animal; Subcutaneous administration; Nutritional status
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2010.110

Objective: To determine the efficacy of a long-acting oxyntomodulin (OXM) analogue, OXM6421, in inhibiting food intake and decreasing body weight in lean and diet-induced obese (DIO) rodents. Research design and methods: The glucagon-like peptide-1 (GLP-1) receptor binding affinity and efficacy, sensitivity to enzymatic degradation in vitro and persistence in the circulation after peripheral administration were investigated for OXM6421 and compared with native OXM. The chronic effect of OXM6421 on food intake, body weight and energy expenditure was examined in lean rats, and its anti-obesity potential was evaluated in DIO mice. Results: OXM6421 showed enhanced GLP-1 receptor binding affinity and cyclic adenosine monophosphate (cAMP) stimulation, and higher resistance to enzymatic degradation by dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase (NEP) compared with native OXM. OXM6421 persisted longer in the circulation than OXM after peripheral administration. Acute administration of OXM6421 potently inhibited food intake in lean rodents, with cumulative effects lasting up to 24 h. In lean rats, daily subcutaneous (s.c.) administration of OXM6421 caused greater weight loss than the pair-fed animals, and a higher rate of oxygen consumption than both the pair-fed and the saline controls. In DIO mice, continuous s.c. infusion of OXM6421 resulted in a significant weight loss, accompanied by an improvement in glucose homeostasis and an increase in circulating adiponectin levels. Once-daily s.c. administration of OXM6421 for 21 days caused sustained weight loss in DIO mice. Conclusion: OXM6421 induces negative energy balance in both lean and obese rodents, suggesting that long-acting OXM analogues may represent a potential therapy for obesity.