HGNC Approved Gene Symbol: PYYCytogenetic location: 17q21.31 Genomic coordinates (GRCh38): 17:43,952,732-44,004,444 (from NCBI)▼ Cloning and ExpressionPeptid...
HGNC Approved Gene Symbol: PYY
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38): 17:43,952,732-44,004,444 (from NCBI)
▼ Cloning and Expression
Peptide YY (PYY) is secreted from endocrine cells in the lower small intestine, colon, and pancreas. It acts on the gastrointestinal tract as an inhibitor of gastric acid secretion, gastric emptying, digestive enzyme secretion by the pancreas, and gut motility (Leiter et al., 1987). The related gene, pancreatic polypeptide (167780), is secreted only by cells within the endocrine and exocrine pancreas and specifically inhibits the secretion of enzymes and bicarbonate from the exocrine pancreas. A third member of this gene family is neuropeptide Y (162640). Each of these proteins is synthesized with a signal peptide sequence followed by a 36-amino acid active peptide and a C-terminal peptide. During maturation, the signal and C-terminal peptides are cleaved and a common C-terminal tyrosine in the mature peptide is amidated. Hort et al. (1995) cloned the human PYY gene by screening a genomic library with a PCR product produced from the rat locus. Based on a comparison of the 3 gene sequences, the authors concluded that NPY and PYY are the result of a gene duplication event, and that a subsequent tandem duplication produced the PPY gene.
▼ Gene Structure
Hort et al. (1995) determined that the PYY gene contains 4 exons spanning about 1.2-kb of DNA. Exon 1 represents 5-prime untranslated sequence and is 75% identical to the comparable rat sequence.
Hort et al. (1995) showed that PYY and PPY are about 10-kb apart and mapped them by fluorescence in situ hybridization to 17q21.
▼ Gene Function
Batterham et al. (2002) demonstrated that peripheral injection of PYY(3-36) in rats inhibits food intake and reduces weight gain. PYY(3-36) also inhibits food intake in mice but not in Y2r (NPY2R; 162642)-null mice, which suggests that the anorectic effect requires the Y2 receptor. Peripheral administration of PYY(3-36) increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy (162640) mRNA. Intraarcuate injection of PYY(3-36) inhibited food intake. PYY(3-36) also inhibited electrical activity of Npy nerve terminals, thus activating adjacent proopiomelanocortin (POMC; 176830) neurons. In humans, infusion of normal postprandial concentrations of PYY(3-36) significantly decreased appetite and reduced food intake by 33% over 24 hours. Thus, postprandial elevation of PYY(3-36) may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.
In common with the adipocyte hormone leptin (164160), PYY reduces food intake by modulating appetite circuits in the hypothalamus. However, in obesity (see 601665) there is a marked resistance to the action of leptin, which greatly limits its therapeutic effectiveness. On the other hand, Batterham et al. (2003) found that obese subjects are not resistant to the anorectic effects of PYY. Endogenous PYY levels were low in obese subjects, suggesting that PYY deficiency may contribute to the pathogenesis of obesity. Korner and Leibel (2003) reviewed, with a useful diagram, the interactions among hormonal and neural pathways that regulate food intake and body fat mass--'how the gut talks to the brain.'
Using functional magnetic resonance imaging, Batterham et al. (2007) showed that PYY modulates neural activity within both corticolimbic and higher-cortical areas as well as homeostatic brain regions. Under conditions of high plasma PYY concentrations, mimicking the fed state, changes in neural activity within the caudolateral orbital frontal cortex predicted feeding behavior independently of meal-related sensory experiences. In contrast, in conditions of low levels of PYY, hypothalamic activation predicted food intake. Thus, Batterham et al. (2007) concluded that the presence of a postprandial satiety factor switches food intake regulation from a homeostatic to a hedonic, corticolimbic area.
Pfluger et al. (2007) studied the effects of acute and chronic changes in human body weight on circulating levels of the putative satiety hormone peptide YY. Total plasma PYY levels (precursor PYY1(1-36) + pharmacologically active PYY(3-36)) were measured in 66 lean, 18 anorectic, 63 obese, and 16 morbidly obese humans. Fasting total plasma PYY levels were highest in patients with anorexia nervosa (80.9 +/- 12.9 pg/ml, P = less than 0.05) compared with lean (52.4 +/- 4.6 pg/ml), obese (43.9 +/- 3.8 pg/ml), or morbidly obese (45.6 +/- 11.2 pg/ml) subjects. Pfluger et al. (2007) concluded that their findings do not support a role for abnormal circulating PYY in human obesity. They also concluded that circulating PYY levels in humans are significantly elevated in anorexia nervosa and, given the controversially discussed anorectic effect of PYY, could theoretically contribute to that syndrome.
▼ Molecular Genetics
For discussion of a possible association between variation in the PYY gene and susceptibility to obesity, see 600781.0001.
▼ ALLELIC VARIANTS ( 1 Selected Example):
.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
This variant, formerly titled OBESITY, SUSCEPTIBILITY TO, has been reclassified because its contribution to susceptibility to obesity has not been confirmed.
Ahituv et al. (2006) sequenced the PYY gene in 379 obese and 378 lean individuals (mean BMI, 49.0 and 19.5, respectively) and identified a gln62-to-pro (Q62P) substitution in the PYY gene at an evolutionarily conserved residue in an isolated obese individual. The Q62P variant was found in 3 obese adults and a nonobese 4-year-old girl with congenital heart disease in an extended family. The authors noted that congenital heart disease might restrict the obesity phenotype. The Q62P variant represents a Q34P change in the secreted form of the peptide; in vitro studies by Keire et al. (2000, 2002) demonstrated that Q34P disrupts the C-terminal helix, causing a major change in the conformation of the peptide and markedly altering the binding of PYY and NPY (162640) to NPY2R. In mouse peptide injection experiments, Ahituv et al. (2006) showed that, whereas wildtype PYY peptide reduced food intake, mutant P34 PYY had an insignificant effect in reducing food intake in vivo, and that coinjection of wildtype and mutant PYY had an effect similar to mutant alone, implying a gain-of-function mechanism that overcomes the wildtype peptide effect. Ahituv et al. (2006) suggested that rare sequence variants within PYY can influence human susceptibility to obesity.