Systemic administration of the long-acting GLP-1 derivative NN2211 induceslasting and reversible weight loss in both normal and obese rats

Postprandial release of the incretin glucagon-like peptide-1 (GLP-1) has be en suggested to act as an endogenous satiety factor in humans. In rats, how ever, the evidence for this is equivocal probably because of very high endo genous activity of the GLP-1 degrading enzyme dipeptidyl peptidase-IV. In t he present study, we show that intravenously administered GLP-1 (100 and 50 0 mug/kg) decreases food intake for 60 min in hungry rats. This effect is p harmacologically specific as it is inhibited by previous administration of 100 mug/kg exendin(9-39), and biologically inactive GLP-1(1-37) had no effe ct on food intake when administered alone (500 mug/kg). Acute intravenous a dministration of GLP-1 also caused dose-dependent inhibition of water intak e, and this effect was equally well abolished by previous administration of exendin(9-39). A profound increase in diuresis was observed after intraven ous administration of both 100 and 500 mug/kg GLP-1. Using a novel long-act ing injectable GLP-1 derivative, NN2211, the acute and subchronic anorectic potentials of GLP-1 and derivatives were studied in both normal rats and r ats made obese by neonatal monosodium glutamate treatment (MSG). We showed previously that MSG-treated animals are insensitive to the anorectic effect s of centrally administered GLP-1(7-37). Both normal and MSG-lesioned rats were randomly assigned to groups to receive NN2211 or vehicle. A single bol us injection of NN2211 caused profound dose-dependent inhibition of overnig ht food and water intake and increased diuresis in both normal and MSG-trea ted rats. Subchronic multiple dosing of NN2211 (200 mug/kg) twice daily for 10 days to normal and MSG-treated rats caused profound inhibition of food intake. The marked decrease in food intake was accompanied by reduced body weight in both groups, which at its lowest stabilized at similar to 85% of initial body weight. Initial excursions in water intake and diuresis were t ransient as they were normalized within a few days of treatment. Lowered pl asma levels of triglycerides and leptin were observed during NN2211 treatme nt in both normal and MSG-treated obese rats. In a subsequent study, a 7-da y NN2211 treatment Period of normal rats ended with measurement of energy e xpenditure (EE) and body composition determined by indirect calorimetry and dual energy X-ray absorptiometry, respectively. Compared with vehicle-trea ted rats, NN2211 and pair-fed rats decreased their total EE corresponding t o the observed weight loss, such that EE per weight unit of lean body mass was unaffected. Despite its initial impact on body fluid balance, NN2211 ha d no debilitating effects on body water homeostasis as confirmed by analysi s of body composition, plasma electrolytes, and hematocrit. This is in cont rast to pair-fed animals, which displayed hemoconcentration and tendency to ward increased percentage of fat mass. The present series of experiments sh ow that GLP-1 is fully capable of inhibiting food intake in rats via a peri pherally accessible site. The loss in body weight is accompanied by decreas ed levels of circulating leptin indicative of loss of body fat. The profoun d weight loss caused by NN2211 treatment was without detrimental effects on body water homeostasis. Thus, long-acting GLP-1 derivatives may prove effi cient as weight-reducing therapeutic agents for overweight patients with ty pe 2 diabetes.