Peptide YY (PYY) and Y2 receptor (Y2R) may be important in the central regulation of body weight and food intake. To determine whether genetic variation in PYY and/or Y2R may contribute to morbid obesity in humans, these genes were sequenced in 83 extremely obese Pima Indians (BMI >50 kg/m 2 ). Sequencing of PYY identified three single nucleotide polymorphsms (SNPs) in the untranslated region. Sequencing of the Y2R coding region identified one missense (Ala172Thr) substitution and two silent substitutions. Eight additional SNPs in the 5 untranslated region of Y2R were identified from public databases. These SNPs were genotyped in 489 fullheritage adult Pimas (362 severely obese and 127 nondiabetic, nonobese subjects), who are not first-degree relatives, for association analysis. The PYY variants were not associated with obesity, whereas four variants from two haplotype blocks in Y2R were marginally associated (P ؍ 0.054 -0.067) with obesity. However, if the analysis was restricted to men (n ؍ 167, 100 obese and 67 lean), the PYY variants and two SNPs in Y2R that were in complete linkage disequilibrium were significantly associated with severe obesity (P ؍ 0.001 and P ؍ 0.002, respectively). Our data suggest that the PYY-Y2R pathway may influence body weight through a sexspecific mechanism, but this finding requires confirmation in other populations. Diabetes 54:1598 -1602, 2005 P eptide YY (PYY), a member of the neuropeptide Y (NPY) family, is a 36 -amino acid peptide secreted from the L-cells of the gastrointestinal tract in response to food intake (1,2). It has been suggested that PYY plays a role in the development of obesity in rodents, but this remains controversial. Peripheral administration of PYY was first reported to decrease food intake in rodents in 1993 (3). PYY3-36, the active form of PYY, also markedly inhibits food intake in rodents (2), and it has been shown to cross the blood-brain barrier and act on the arcuate nucleus of the hyperthalamus (4,5). PYY3-36 has a high affinity for the Y2 receptor (Y2R) (2,6), and animal studies have shown that PYY3-36 inhibits hypothalamic NPY-expressing neurons by binding to Y2R (7). Mice lacking the Y2R gene have increased body weight, food intake, and fat deposition (8). In contrast to these studies, Tschö p et al. (9) recently reported that PYY3-36 does not decrease food intake in rodents.It has also been suggested that the PYY/Y2R pathway plays a role in human obesity. Peripheral administration of PYY3-36 was reported to inhibit food intake in humans (10), and plasma PYY concentrations were decreased in obese compared with lean subjects (10). In addition, two synonymous amino acid substitutions have been identified in Y2R that are associated with obesity in British Caucasian men (11).The Pima Indians of Arizona have a high prevalence of severe obesity, and BMI in this population is highly heritable (12,13). As part of our genetic studies to identify variation in genes that affect body weight in this NativeAmerican population, PYY and Y2R were analyzed...