MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, Shows Differential Brain Activation vs. Liraglutide in Mice

MEDI0382 is under development for the treatment of type 2 diabetes. MEDI0382 reduces food intake and body weight in obese mice and primates. In rodents, the weight-reducing effects of MEDI0382 are superior to those of the GLP-1 analogue, liraglutide. The current study characterised the activation of distinct neuroanatomical areas following peripheral administration of MEDI0382, relative to liraglutide and the glucagon receptor agonist, G1432. C57Blk6 mice were fasted for 4 h and then injected with a single dose (3 nmol/kg; s.c) of test agent or vehicle (n=4 each). After 2 h, mice were sacrificed and brains were dissected out and immersion-fixed in formalin (24-48 h). The brains were then cut into 3 mm serial slices and processed to paraffin blocks. Each block was sectioned entirely, sampling a 4µm step section every 100µm. Each section was immunohistochemically stained for c-fos, using a rabbit anti-fos polyclonal, with haematoxylin counterstain. Stained sections were digitally scanned at 20x magnification (Aperio AT2). The appropriate brain sections containing the area postrema (AP), the nucleus of the solitary tract (NTS), and the hypothalamic parabrachial (PBN) and arcuate nuclei were selected. These areas were manually delimited using the online Allen mouse brain atlas. The number of positive and negative nuclei were automatically counted (Halo), and reported as % of total positive cells and number of cells per tissue area. MEDI0382 significantly increased c-fos activation in the AP and NTS vs. vehicle, whereas liraglutide and G1432 showed no difference from vehicle. There was no significant increase in c-fos activation in the arcuate nucleus or PBN in any treatment group when compared to vehicle. In summary, the neuronal activation by MEDI0382 shows that distinct differences were observed compared to GLP-1 and glucagon agonists alone, suggesting that a different pattern of activation exists for the dual agonist, MEDI0382 vs. the monotherapies. Disclosure L.K. Burke: None. L. Brown: Stock/Shareholder; Self; AstraZeneca. J. Lapointe: Employee; Self; MedImmune. M. Sulikowski: None. A.R. Lewis: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. D. Baker: Stock/Shareholder; Self; AstraZeneca.