The escalating burden of obesity reflects a global pandemic affecting developed and developing countries. Current anti-obesity strategies have failed due to limited efficacy and or adverse side effects. There is an unmet need for effective therapies. Inhibitors of the enzyme Methionine Aminopeptidase-2 (MetAP2) were developed as anti-cancer agents but more recent investigations have repositioned them as anti-obesity therapeutics. Studies in obese preclinical models demonstrate that treatment with MetAP2 inhibitors leads to weight loss via reduced food intake and enhanced metabolism. A phase I clinical trial in obese adult women demonstrated that Beloranib was well-tolerated and promoted significant weight loss at the highest dose (0.9 mg/m2; -3.8 kg vs. -0.6 kg with placebo; n=8 & 6).
Inhibitors of MetAP2 are known to increase MetAP2 binding to ERK and eIF2α resulting in decreased phosphorylation/activation. The activity of c-Src, recently implicated as a key protagonist in the aetiology of obesity-related inflammation, is dependent on MetAP2 activity for efficient cleavage and subsequent N-terminal myristoylation. We hypothesised that MetAP2 inhibitors mediate their effects via modulation of multiple signalling pathways reducing inflammation and or ER stress.
We have used Western blot, Alphascreen and immunofluorescence microscopy to investigate the effects of MetAP2 inhibitor treatment in vivo and in vitro. In obese mice, treatment with a MetAP2 inhibitor decreased liver phospho-ERK (p<0.001) as well as phospho-P38MAPK (p<0.05) and showed a trend towards reduced phospho-eIF2α. These effects were not observed in subcutaneous or mesenteric adipose tissue. In vitro studies performed in HUVECs demonstrated that MetAP2 inhibitor treatment reduced EGF-stimulated phosphorylation of ERK and c-Src but not TNFα-stimulated phosphorylation of p38MAPK.
These results suggest that MetAP2 inhibitors represent a novel class of potentially effective anti-obesity agents. Further work is required to tease out the mechanisms that underpin the beneficial effects with the former likely to reflect pleiotropic, tissue/cell-type specific effects.