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


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.


CONCLUSIONS
OXM6421 induces negative energy balance in both lean and obese rodents, suggesting that long-acting OXM analogues may represent a potential therapy for obesity.
Department of Investigative Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital, London, UK.
Y-L
YL
Liu
H E
HE
Ford
M R
MR
Druce
J S
JS
Minnion
B C T
BC
Field
J C
JC
Shillito
J
J
Baxter
K G
KG
Murphy
M A
MA
Ghatei
S R
SR
Bloom
D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects* / Q000502:physiology; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005768:Gastrointestinal Hormones / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D036361:Peptide Hormones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000187:drug effects*; D015431:Weight Loss / Q000187:drug effects / Q000502:physiology
D019440:Anti-Obesity Agents; D005768:Gastrointestinal Hormones; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; C557493:OXM 6421; D036361:Peptide Hormones; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1