Systemic Administration of the Long-Acting GLP-1 Derivative NN2211 Induces Lasting and Reversible Weight Loss in Both Normal and Obese Rats

Systemic Administration of the Long-Acting GLP-1 Derivative NN2211 Induces Lasting and Reversible Weight Loss in Both Normal and Obese Rats Philip J. Larsen 1 2 , Christian Fledelius 3 , Lotte Bjerre Knudsen 4 and Mads Tang-Christensen 1 1 Laboratory of Obesity Research, Center for Clinical and Basic Research, Ballerup, Denmark 2 Neuroendocrine Pharmacology 3 Pharmacological Research 2, and 4 Molecular Pharmacology, Novo Nordisk A/S, Copenhagen, Denmark Abstract 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 triglyce