Systemic Administration of the Long-Acting GLP-1 Derivative NN2211 Induces Lasting and Reversible Weight Loss in Both Normal and Obese Rats
- 1Laboratory of Obesity Research, Center for Clinical and Basic Research, Ballerup, Denmark
- 2Neuroendocrine Pharmacology
- 3Pharmacological Research 2, and
- 4Molecular Pharmacology, Novo Nordisk A/S, Copenhagen, Denmark
Postprandial release of the incretin glucagon-like peptide-1 (GLP-1) has been suggested to act as an endogenous satiety factor in humans. In rats, however, the evidence for this is equivocal probably because of very high endogenous activity of the GLP-1 degrading enzyme dipeptidyl peptidase-IV. In the present study, we show that intravenously administered GLP-1 (100 and 500 μg/kg) decreases food intake for 60 min in hungry rats. This effect is pharmacologically specific as it is inhibited by previous administration of 100 μg/kg exendin(9-39), and biologically inactive GLP-1(1-37) had no effect on food intake when administered alone (500 μg/kg). Acute intravenous administration of GLP-1 also caused dose-dependent inhibition of water intake, and this effect was equally well abolished by previous administration of exendin(9-39). A profound increase in diuresis was observed after intravenous administration of both 100 and 500 μg/kg GLP-1. Using a novel long-acting injectable GLP-1 derivative, NN2211, the acute and subchronic anorectic potentials of GLP-1 and derivatives were studied in both normal rats and rats made obese by neonatal monosodium glutamate treatment (MSG). We showed previously that MSG-treated animals are insensitive to the anorectic effects 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 bolus injection of NN2211 caused profound dose-dependent inhibition of overnight food and water intake and increased diuresis in both normal and MSG-treated rats. Subchronic multiple dosing of NN2211 (200 μg/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 ∼85% of initial body weight. Initial excursions in water intake and diuresis were transient as they were normalized within a few days of treatment. Lowered plasma levels of triglycerides and leptin were observed during NN2211 treatment in both normal and MSG-treated obese rats. In a subsequent study, a 7-day NN2211 treatment period of normal rats ended with measurement of energy expenditure (EE) and body composition determined by indirect calorimetry and dual energy X-ray absorptiometry, respectively. Compared with vehicle-treated rats, NN2211 and pair-fed rats decreased their total EE corresponding to 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 had no debilitating effects on body water homeostasis as confirmed by analysis of body composition, plasma electrolytes, and hematocrit. This is in contrast to pair-fed animals, which displayed hemoconcentration and tendency toward increased percentage of fat mass. The present series of experiments show that GLP-1 is fully capable of inhibiting food intake in rats via a peripherally accessible site. The loss in body weight is accompanied by decreased levels of circulating leptin indicative of loss of body fat. The profound weight loss caused by NN2211 treatment was without detrimental effects on body water homeostasis. Thus, long-acting GLP-1 derivatives may prove efficient as weight-reducing therapeutic agents for overweight patients with type 2 diabetes.
Address correspondence and reprint requests to Philip J. Larsen, Dr, MSci, Laboratory of Obesity Research, Centre for Clinical and Basic Research, Ballerup Byvej 222, 2750 Ballerup, Denmark. E-mail:.
Received for publication 24 January 2001 and accepted in revised form 26 July 2001.
L.B.K and C.F. are employees of and hold stock in Novo Nordisk.
ANOVA, analysis of variance; DEXA, dual energy X-ray absorptiometry; DPP-IV, dipeptidyl peptidase-IV; EE, energy expenditure; FFA, free fatty acids; GLP-1, glucagon-like peptide-1; MSG, monosodium glutamate; RER, respiratory exchange ratio; TG, triacylglycerol.