Drug development for obesity has been fraught with failures and false-starts, in part owing to the complex pathways that govern energy homeostasis. One strategy is to intervene in key pathways using synthetic agents that mimic the action of endogenous molecules. Decara et al. now report that elaidyl-sulfamide, a molecule based on the anorectic lipid oleoylethanolamide (OEA), reduces food intake, body weight, plasma cholesterol and markers of hepatic dysfunction in obese rats. Similar to OEA, elaidyl-sulfamide was found to act as a PPARα agonist. However, in line with the ability of OEA to negatively regulate insulin signalling, chronic elaidyl-sulfamide treatment induced insulin resistance. This study suggests that chemical modelling of OEA is a promising avenue for drug development, providing that the effects of related compounds on insulin signalling can be overcome or are found to be negligible in humans. Page 660
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