Over the past decade a large number of targets have been advanced for the treatment of obesity. This is unsurprising considering the incidence of this condition and the prediction that the world obesity market will reach $3.7 billion by 2008. Current pharmaceutical approaches to obesity have largely focused on the development of centrally acting molecules that modify hunger, reward or satiety and Abbott's sibutramine (Reductil/Meridia), a 5-HT and norepinephrine reuptake inhibitor leads the field in this respect.

Neuropeptide Y (NPY) levels are chronically elevated in the hypothalamus of genetically obese ob/ob mice, while on the other hands, intracerebroventricular administration of NPY produces a pronounced feeding response in a variety of species and under in satiated conditions. Unsurprisingly therefore many therapeutic targets for the treatment of obesity are related to hypothalmic neuropeptide Y pathways. A good example of this can be found in ghrelin, one of the most promising targets to emerge in the field of obesity in recent years. The ghrelin story started in the mid-1990’s when a number of synthetic growth hormone secretagogues were found to act at a novel receptor in the pituitary and hypothalamus. It was later found that that almost all NPY-expressing nerve fibers in the arcuate hypothalamic nuclei expressed this receptor and in 1999 ghrelin was identified as a natural ligand for this receptor. Since then a large body of data has emerged to support the concept that ghrelin plays a central role in food intake and that ghrelin receptor antagonists may be of use in the treatment of obesity (for a full analysis of this field click here). As an alternative to targeting molecules that modulate the activity of NPY containing fibers, the development of NPY receptor antagonists may be of considerable benefit as anorectics. The actions of NPY are believed to be mediated by a family of receptor subtypes named Y1 - y6 and it is now believed that antagonists of one or more of these receptors may confer anorectic activity. In particular since NPY stimulates food intake, inhibits energy expenditure, increases body weight and increases anabolic hormone levels by activating the NPY Y(1) and Y(5) receptors in the hypothalamus, several antagonists of these receptors have been developed recently as potential anti-obesity agents. Related to the problem of obesity is a two-fold increase in the risk of developing insulin resistance and diabetes and NPY has been related to this phenomenon since when administered centrally, NPY induces hyperinsulinemia and insulin resistance. Australian researchers have now shown that crossing the Y2 receptor knockout mouse onto the ob/ob background attenuates the increased adiposity, hyperinsulinemia and hyperglycemia of ob/ob mice. Compared with lean controls, ob/ob mice had decreased expression of proopiomelanocortin (POMC). Y2 deletion in ob/ob mice significantly increased the hypothalamic POMC expression. Knock-out mice were no different from ob/ob littermates with respect to food intake and body weight, suggesting that while Y1 and Y5 receptors may be responsible for increased food intake, Y2 receptors mediate the obese type 2 diabetes phenotype of ob/ob mice, possibly via alterations in melanocortin signaling in the arcuate nucleus. Thus, the ability of NPY to cause increased food intake and insulin resistance may be due to divergent pathways activated by different NPY receptors. To optimize therapeutic efficacy, NPY antagonists may therefore need to target NPY2 as well as NPY1/5 receptors.

Entry date January, 2003

Adapted from Sainsbury et al, Diabetes 2002 Dec;51(12):3420-7 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.