Research Notes: Neuropeptide Y (NPY)

(10/03/06 - EurekAlert) Promising anti-obesity drug fails to produce clinically meaningful weight loss.

A drug designed to target a powerful hunger-stimulating factor that has long been considered a prime target for antiobesity therapy failed to produce clinically meaningful weight loss in obese people in a long-term clinical trial. People taking the drug known as MK-0557 for a year consistently lost about three pounds more than those taking a placebo, researchers reported in the October issue of the journal Cell Metabolism.

The results, which are the culmination of a 10 year program of study, suggest MK-0557 alone will not provide a useful weapon in the fight against obesity. The possibility remains, however, that the treatment could potentially play a role in future combination therapies, according to the research team that includes Steven Heymsfield and Ngozi Erondu of Merck & Co., Inc. "The current findings add to a growing sense that you will have to try a lot of different targets or get an even better understanding of the scientific underpinnings in order to unwire the food intake system with some combination of drugs," Steven Heymsfield said. "Finding safe and effective antiobesity drugs is not unlike the challenge and complexity of sending the space shuttle into orbit."

MK-0557 blocks brain receptors that respond to the hunger factor called neuropeptide Y (NPY). NPY, whose role in driving appetite Heymsfield likens to an accelerator in a car, is one in a chain of players in the hunger pathway that includes the fat hormone leptin. Leptin hormone sends signals to the brain about the level of energy stores available, information that is then used to gauge metabolism and appetite.

Scientists discovered NPY more than two decades ago, making it one of the first identified appetite stimulants, but it was only after the discovery of leptin in 1994 that the neuropeptide's key role and potential as a drug target was fully appreciated. After screening numerous compounds for their safety and ability to specifically bind NPY receptors, MK-0557 emerged as the "survivor," Heymsfield said.

In the current study, the researchers first conducted a unique imaging study designed to directly reveal the number of human NPY receptors bound by MK-0557 after people took the drug at various doses. Using this method, they found that it only takes a small amount - 1 mg per day - for almost complete occupancy of the "NPY5R" receptor.

A 12 week proof-of-concept and dosing study including 547 participants taking either a placebo or the drug at doses ranging from 0.2-25 mg/day supported the imaging study's findings, the researchers reported. MK-0557 was found to be well tolerated and to induce modest weight loss in obese individuals. The amount of weight loss and proportion of receptors bound by the drug reached a plateau at doses greater than 1 mg.

The results led the researchers to proceed with a year long clinical trial including 1661 patients randomized into placebo or 1 mg MK-0557 groups, in order to test whether the drug would support continued weight loss. Of the 832 participants who successfully completed the trial, those in the placebo group lost an average of about 4 pounds, while those taking MK-0557 lost about 7.5 pounds. While the weight loss difference between groups was found to be statistically significant, the results "strongly suggest that a highly selective NPY5R antagonist" on its own is insufficient treatment for curbing obesity, Heymsfield reported.

The findings in some ways mirror earlier studies that looked to leptin as a "magic bullet" for weight loss therapy, Heymsfield said. "Most obesity was found to be insensitive to leptin," he said. "It appears the same is true for the NPY5R pathway. When you hit this receptor as a single target, it doesn't generally appear to change energy balance profoundly."

Growth Horm IGF Res. 2003 Dec.
Peptides associated with hyperphagia in adults with Prader-Willi syndrome before and during GH treatment.
Hoybye C, Barkeling B, Espelund U, Petersson M, Thoren M.
Department of Endocrinology and Diabetology, Karolinska Hospital, Stockholm, Sweden.

Prader-Willi syndrome (PWS) is a complex genetic disorder characterised by mild mental retardation and distinct physical, behavioural, and psychiatric features. One of the cardinal symptoms is excessive eating, which - if left untreated - leads to extreme obesity. In the present study we have examined circulating levels of peptides with documented association to hyperphagia in young adults with PWS. Since growth hormone (GH) is often used nowadays to correct GH insufficiency during childhood PWS, we also studied the impact of GH administration on the peptides. Seventeen adults, 9 men and 8 women, 17-32 years of age with a mean BMI of 35+/-3.2 kg/m(2) participated. All had clinical PWS (Holm's criteria). Genetic testing was performed in all patients and in 11 the diagnosis was confirmed. They were randomized to treatment with either placebo or GH (Genotropin, Pharmacia Corporation) for 6 months. Subsequently all received open label treatment to provide all subjects with 12 months active GH treatment. Doses were individually titrated. Weight, BMI, oxytocin (baseline only), leptin, Neuropeptide Y (NPY), and ghrelin were evaluated at baseline and after 6 and 12 months. At baseline plasma mean oxytocin was within and serum ghrelin just above the normal range (14.7+/-1.2 pmol/L and 0.87+/-0.12 microg/L, respectively). Serum leptin levels were high above and plasma NPY levels within the lower normal range (47.8+/-29.1 microg/L and 13+/-1 pmol/L, respectively). Results were independent of genotype. No changes in mean BMI, ghrelin, leptin or NPY were seen following GH treatment. Conclusion: Leptin levels were in general high reflecting obesity and as a consequence NPY levels were low. In simple obesity oxytocin levels are high, while ghrelin levels are suppressed. In view of the adiposity oxytocin circulated in abnormally low and ghrelin in abnormally high concentrations in our patients. GH treatment of PWS patients did not change ghrelin, leptin or NPY. We suggest that both oxytocin and ghrelin are involved in the pathogenesis of hyperphagia seen in PWS.