Sustained and Reversible Weight Reduction with Long-Acting GLP-1 Analog NN2211 in Rats

The incretin hormone glucagon-like peptide-1 (GLP-1) is recognized for its potential role in promoting satiety in humans, but its role in rats has been less clear due to their high endogenous activity of the GLP-1 degrading enzyme, dipeptidyl peptidase-IV. This study demonstrates that intravenous administration of GLP-1 reduces food intake in hungry rats, an effect that is blocked by exendin(9-39), indicating pharmacological specificity. Additionally, GLP-1 inhibits water intake and increases diuresis in a dose-dependent manner.

A long-acting GLP-1 derivative, NN2211, was tested for its anorectic potential in both normal and obese rats induced by neonatal monosodium glutamate (MSG) treatment. Both single and multiple dosing of NN2211 significantly reduced food and water intake and increased diuresis without causing detrimental effects on body water homeostasis. The treatment led to a decrease in body weight, accompanied by reduced plasma levels of triglycerides and leptin, suggesting a loss of body fat.

In a separate study, normal rats treated with NN2211 for seven days showed a decrease in total energy expenditure that corresponded to their weight loss, without affecting energy expenditure per unit of lean body mass. Unlike pair-fed animals, which exhibited hemoconcentration and a tendency toward increased fat mass, NN2211-treated rats did not display these adverse effects.

The experiments indicate that GLP-1, when delivered via a long-acting derivative like NN2211, can effectively inhibit food intake in rats and may have potential as a weight-reducing therapeutic for overweight patients with type 2 diabetes, without negatively impacting body water homeostasis.