Treating obesity: Does antagonism of NPY fit the bill?
2006; Cell Press; Volume: 4; Issue: 4 Linguagem: Inglês
10.1016/j.cmet.2006.09.006
ISSN1932-7420
Autores Tópico(s)Adipose Tissue and Metabolism
ResumoIn this issue of Cell Metabolism, Erondu et al., 2006Erondu N. Gantz I. Musser B. Suryawanshi S. Mallick M. Addy C. Cote J. Bray G. Fujioka K. Bays H. et al.Cell Metab. 2006; 4 (this issue): 275-282Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar identify a selective neuropeptide Y5 receptor antagonist that, as predicted from rodent studies, results in weight loss when administered to overweight and obese human subjects. In a one-year randomized placebo-controlled clinical trial, the weight loss was modest; the results support the emerging concept that NPY acts via overlapping and redundant energy homeostasis pathways. In this issue of Cell Metabolism, Erondu et al., 2006Erondu N. Gantz I. Musser B. Suryawanshi S. Mallick M. Addy C. Cote J. Bray G. Fujioka K. Bays H. et al.Cell Metab. 2006; 4 (this issue): 275-282Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar identify a selective neuropeptide Y5 receptor antagonist that, as predicted from rodent studies, results in weight loss when administered to overweight and obese human subjects. In a one-year randomized placebo-controlled clinical trial, the weight loss was modest; the results support the emerging concept that NPY acts via overlapping and redundant energy homeostasis pathways. Given the disease burden and health costs associated with the rising prevalence of obesity and associated comorbidities such as type 2 diabetes, there is a growing need to find effective, safe, and well-tolerated therapies to treat obese patients (Flegal et al., 1998Flegal K.M. Carroll M.D. Kuczmarksi R.J. Johnson C.L. Int. J. Obes. Relat. Metab. Disord. 1998; 22: 39-47Crossref PubMed Scopus (2469) Google Scholar). Although currently available antiobesity medications are modestly effective, in some subjects they are accompanied by significant adverse effects. In recent years, substantial advances have been made in the understanding of central pathways involved in the regulation of feeding behavior and energy homeostasis (Schwartz et al., 2000Schwartz M.W. Woods S.C. Porte Jr., D. Seeley R.J. Baskin D.G. Nature. 2000; 404: 661-671Crossref PubMed Scopus (4653) Google Scholar). Many of the agents presently in early-stage clinical trials act on these central pathways, reflecting the consensus that the brain exerts a major influence on feeding behavior and peripheral metabolism through the autonomic nervous system. In this issue, Erondu et al., 2006Erondu N. Gantz I. Musser B. Suryawanshi S. Mallick M. Addy C. Cote J. Bray G. Fujioka K. Bays H. et al.Cell Metab. 2006; 4 (this issue): 275-282Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar present data on the first clinical trial of an orally administered neuropeptide Y5 receptor (NPY5R) antagonist. They show efficacy in terms of weight loss at 12 weeks and in an extended study at 52 weeks. However, the amount of weight lost in the long-term study was not sufficiently clinically significant for the agent to be considered as a feasible monotherapy for obesity. Neuropeptide Y (NPY) contains 36 amino acid residues and is one of the most abundant peptides in the brain. Although NPY has been implicated in cardiovascular regulation, the control of neuroendocrine axes, affective disorders, seizures, and memory retention, its most noticeable effect is the stimulation of food intake after central administration, and it is one of the most potent orexigenic peptides known (Lin et al., 2004Lin S. Boey D. Herzog H. Neuropeptides. 2004; 38: 189-200Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). When administered chronically, NPY produces an increase in food intake, decreased thermogenesis, and obesity. The hypothalamic arcuate nucleus (ARC) is the major site of expression for NPY within neurons that project to the paraventricular nucleus (PVN), dorsomedial hypothalamus (DMH), and lateral hypothalamus (LH) as well as other sites. NPY synthesis and secretion are upregulated in energy-deficient states such as starvation, lactation, and physical exercise and in rodent models that lack leptin (ob/ob mice) and its receptor (db/db mice) (Lin et al., 2004Lin S. Boey D. Herzog H. Neuropeptides. 2004; 38: 189-200Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). Fasting activates the NPY neurons that express the long signaling isoform of the leptin receptor (Baskin et al., 1999Baskin D.G. Breininger J.F. Schwartz M.W. Diabetes. 1999; 48: 828-833Crossref PubMed Scopus (277) Google Scholar); a primary physiological role for the arcuate NPY neurons may thus be to restore normal energy balance and body fat stores under conditions of energy deficit, the signals of which are falling leptin and/or insulin (Schwartz et al., 2000Schwartz M.W. Woods S.C. Porte Jr., D. Seeley R.J. Baskin D.G. Nature. 2000; 404: 661-671Crossref PubMed Scopus (4653) Google Scholar). Inhibition of the synthesis of NPY in the ARC and its subsequent release into the PVN, the most abundant projection, may thus partly explain the ability of leptin to induce hypophagia and weight loss (Figure 1). NPY and its two other family members, peptide YY (PYY) and pancreatic polypeptide (PP), exert their effects through five known G protein-coupled receptors: Y1, Y2, Y4, Y5, and Y6 (Fetissov et al., 2004Fetissov S.O. Kopp J. Hokfelt T. Neuropeptides. 2004; 38: 175-188Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Although the large number of Y receptors has made it difficult to delineate their individual contributions, recent studies analyzing NPY and Y receptor-overexpressing, knockout, and conditional-knockout mouse models have started to unravel some of the complexity (Lin et al., 2006Lin E.J. Sainsbury A. Lee N.J. Boey D. Couzens M. Enriquez R. Slack K. Bland R. During M.J. Herzog H. Endocrinology. 2006; (Published online July 27, 2006)https://doi.org/10.1210/en.2006-0097Crossref Scopus (47) Google Scholar). Analogs of NPY with high selectivity for the Y1 and Y5 receptor subtypes strongly stimulate food intake in rodents, and i.c.v. administration of specific Y5 receptor agonists increases food intake and body weight in mice (Parker et al., 2000Parker E.M. Balasubramaniam A. Guzzi M. Mullins D.E. Salisbury B.G. Sheriff S. Witten M.B. Hwa J.J. Peptides. 2000; 21: 393-399Crossref PubMed Scopus (74) Google Scholar). Erondu et al., 2006Erondu N. Gantz I. Musser B. Suryawanshi S. Mallick M. Addy C. Cote J. Bray G. Fujioka K. Bays H. et al.Cell Metab. 2006; 4 (this issue): 275-282Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar report the first studies in humans using the selective NPY5R antagonist MK-0557. They show that this compound selectively binds to the Y5R in the nanomolar range in vitro, with no selective binding to the other NPY receptor subtypes. They observe some nonselective binding at the adenosine A1 receptor, the serotonergic 5HT2B receptor, and a monoamine transporter in the micromolar range, although whether this binding would have any physiological relevance is unclear. In lean mice fed a high-fat (31%) diet, MK-0557 caused a 40% reduction in body weight gain (rather than weight loss) and a 5% reduction in cumulative food intake compared to control mice. Following on from these preclinical studies, the authors went on to demonstrate in vivo receptor occupancy by imaging the brain in human volunteers using positron emission tomography (PET) following the administration of a radiolabeled NPY5R-selective PET ligand with a structure similar to MK-0557. These data were consistent with their pharmacokinetic data and guided the choice of optimal dosing for their subsequent clinical studies. After a 6 week run in with dietary and exercise advice, as is conventional in clinical trials of weight-loss medication, the authors administered MK-0557 to 547 obese subjects, who showed statistically significant weight loss at 12 weeks compared to subjects treated with placebo. These observations clearly indicate that antagonizing the Y5R induces weight loss in humans. The authors then undertook a long-term trial over 52 weeks in 1661 subjects (832 completed). Primary endpoints used to evaluate antiobesity drugs most frequently include mean weight loss, percentage weight loss, and proportion of patients losing ≥5% and ≥10% of initial body weight; secondary endpoints conventionally include reduction in body fat, risk factors for cardiovascular disease, and the incidence of diseases such as type 2 diabetes. A major obstacle to the evaluation of weight-loss clinical trials is the potential bias resulting from low study completion rates, and this effect may well be relevant in the trials conducted by Erondu et al. Other inherent potential sources of bias include run-in periods and subsequent patient selection based on compliance or initial weight loss (Patel et al., 2006Patel R.M. Donahue M. Wilson P.W. Califf R.M. Am. Heart J. 2006; 151: 633-642Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). Nonetheless, Erondu et al. showed a mean weight loss of 3.4 kg in those who completed the trial, which was significantly greater than the weight loss seen in the placebo-treated group over 52 weeks. Significantly more subjects lost ≥5% and ≥10% of initial body weight with the NPY5R antagonist than did so on placebo. The authors conclude, however, that the magnitude of the weight loss observed was not clinically significant, and this conclusion is supported by the observation that there were no significant improvements in secondary endpoints such as glucose and lipid levels and blood pressure measurements. Are these results unexpected? As the authors point out, it is well known that the NPY-mediated feeding response may be mediated by more than one receptor subtype, and biological redundancies are likely to exist between Y1 and Y5 receptor signaling (Parker et al., 2002Parker E. Van Heek M. Stamford A. Eur. J. Pharmacol. 2002; 440: 173-187Crossref PubMed Scopus (82) Google Scholar). In a recent study by Herzog and colleagues (Lin et al., 2006Lin E.J. Sainsbury A. Lee N.J. Boey D. Couzens M. Enriquez R. Slack K. Bland R. During M.J. Herzog H. Endocrinology. 2006; (Published online July 27, 2006)https://doi.org/10.1210/en.2006-0097Crossref Scopus (47) Google Scholar), long-term hypothalamic overexpression of NPY in mice resulted in a marked increase in food intake and weight gain that persisted in Y1 and Y2 receptor knockouts, Y2/Y4 double knockouts, and Y1/Y2/Y4 triple knockouts. Also, increasing evidence points to the existence of other as yet unidentified Y receptors, which may mediate NPY's orexigenic actions, and it remains possible that, under certain physiological conditions, NPY may bind and activate receptors for which it normally has no or only low affinities. The only drugs currently approved for the management of obesity in adults are sibutramine, orlistat, and, more recently, rimonabant, each of which has been demonstrated to be effective in long-term randomized controlled trials. While several potential new obesity therapies that act through the CNS pathways or peripheral adiposity signals are in early-phase clinical trials, the study by Erondu et al., 2006Erondu N. Gantz I. Musser B. Suryawanshi S. Mallick M. Addy C. Cote J. Bray G. Fujioka K. Bays H. et al.Cell Metab. 2006; 4 (this issue): 275-282Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar serves to remind us that manipulation of the homeostatic mechanisms involving hypothalamic/brainstem pathways for a clinically significant outcome in obese patients remains a major challenge. Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adultsErondu et al.Cell MetabolismOctober, 2006In BriefNeuropeptide Y (NPY) is a potent orexigenic neuropeptide, and antagonism of NPY Y1 and NPY Y5 receptors (NPYxR) is considered a potentially important anti-obesity drug target. We tested the hypothesis that blockade of the NPY5R will lead to weight loss in humans using MK-0557, a potent, highly selective, orally active NPY5R antagonist. The initial series of experiments reported herein, including a multiple-dose positron-emission tomography study and a 12 week proof-of concept/dose-ranging study, suggested an optimal MK-0557 dose of 1 mg/day. Full-Text PDF Open Archive
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