Peptide YY: obesity's cause and cure?

RECENTLY, the United States Food and Drug Administration (FDA) decided for the present against approving the cannabinoid receptor antagonist Rimonabant for the treatment of obesity in the United States. This decision resulted mainly from concerns based on studies showing that the drug’s benefits would not outweigh its risks for side effects. This decision further diminished already limited hopes that a potent and safe antiobesity drug would soon emerge and remove one of the most serious health threats to industrialized and developing societies of today and tomorrow. What would a new drug candidate need to have to become a perfect antiobesity agent? Such a perfect antiobesity molecule should not only lead to sustained loss of body fat but also induce the necessary negative energy balance without causing undesired side effects. Moreover, a perfect antiobesity agent would preferably be a naturally occurring, endogenous molecule, and it should target a known specific mechanism. Finally, it should remove the cause of obesity rather than treat symptoms of the disease. Looking at these requirements, it seems that such a silver bullet may already be available: the gastrointestinal hormone peptide YY (PYY). On the basis of published data, PYY may be the only currently known molecule that matches these criteria without exception: PYY has been reported to induce a negative energy balance by potently decreasing food intake in rodents (16) and humans (17) without causing any undesired side effects (16, 17). This gut peptide is a naturally occurring hormone that is secreted by endocrine L cells of the colon (28). The reported mechanism of action of its predominantly circulating form, PYY3-36, is based on the specific activation of hypothalamic NPY-Y2 autoreceptors leading to increased firing of satietyinducing proopiomelanocortin (POMC) neurons (16). Based on the morbidly obese phenotype of PYY-deficient mice (15), PYY has also been considered the most potent satiety factor of the gastrointestinal system. Finally, PYY also uniquely represents the possible cause of obesity as well as its ultimate cure, since obese individuals have been found to be PYY deficient (9, 15) but do not seem to be resistant to PYY replacement therapy (17). In other words, the gut hormone PYY seems to be the perfect antiobesity drug. So why has the extensive search for efficient and safe antiobesity agents not been called off yet? One reason may have been that a series of follow-up studies painted an unusually contradictory picture. According to various reports, PYY3-36 did not induce a negative energy balance or decrease body weight in rodents (1, 2, 10), but causes visceral illness and conditioned taste aversion (27). In follow-up studies, PYY’s effects were not found to be mediated by satietypromoting POMC neurons (26), since PYY3-36 actually decreases their activity (25), and three other reports on PYYdeficient mouse models (5, 11, 13) failed to detect a substantial role in energy balance regulation. Finally, recent studies have demonstrated that obese individuals are not PYY deficient (19, 20, 21, 24), and the first clinical trial reported that PYY infusion in humans was not side-effect free but did induce nausea and vomiting (18). In other words, depending on the selection of published studies, the gut hormone PYY may fulfill all—or none—of the criteria for an attractive antiobesity drug candidate. Inconsistent, or even contradictory, results are not a rarity in the fast-paced search for novel metabolic drug treatments, although the number of controversially discussed issues surrounding PYY seems to be above average. There are numerous potential causes for the observed inconsistencies between datasets, most of which have to do with a combination of small but important differences in the respective experimental designs. Varying validity and reliability of the specific tools and assays used in these different studies also likely contributed to the variability of the outcome. A better understanding of these details will not only be important for a more reliable analysis of the antiobesity potential of PYY but should also provide important advancement for efficient and meaningful use of preclinical metabolic disease models in general. Independent of that, however, independent and large-size human studies represent the most definite way to examine the value of PYY as a drug candidate. Recently, three clinical trials testing PYY were reported, two of them in this journal (American Journal of Physiology Endocrinology and Metabolism) (3, 6, 7). Sloth et al. started by administering the two main circulating forms of PYY (PYY1-36 and PYY3-36; PYY3-36 at 0.8 pmol kg 1 min ) intravenously over 90 min in 12 lean and 12 obese male subjects in a blinded, randomized crossover study (6). The study design and the concentration of PYY3-36 were chosen to repeat the originally reported design leading to substantial reductions in food intake (16, 17). The main observations in this new study were that food intake was reduced, but, due to severe nausea, only four participants completed the infusion of PYY3-36 (6). Increases in insulin, postprandial glucose, energy expenditure, and heart rate were interpreted as signs of increased sympathoadrenergic drive. After the dose of PYY3-36 was reduced by 75%, effects on food intake disappeared, and side effects, including nausea, were reduced. PYY1-36 was better tolerated but failed to reduce food intake, even after doubling the dose. In a follow-up study, Sloth et al. refined their study design on the basis of the previously observed results (7) by looking at the effect of escalating injections of subcutaneous doses of PYY on food intake in healthy human volunteers. In this blinded, placebo-controlled crossover study, they were unable to find a decrease in food intake following injection of PYY, but they did observe significant levels of nausea and vomiting Address for reprint requests and other correspondence: M. H. Tschöp, Dept. of Psychiatry, Obesity Research Center and Genome Research Institute, Univ. of Cincinnati College of Medicine, Cincinnati, OH (e-mail: tschoemh @ucmail.uc.edu). Am J Physiol Endocrinol Metab 293: E1131–E1133, 2007; doi:10.1152/ajpendo.00568.2007.