Ahituv Nadav, Kavaslar Nihan, Schackwitz Wendy, Ustaszewska Anna, Collier John Michael, Hébert Sybil, Doelle Heather, Dent Robert, Pennacchio Len A, McPherson Ruth
Genomics Division, One Cyclotron Road, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Hum Mol Genet. 2006 Feb 1;15(3):387-91. doi: 10.1093/hmg/ddi455. Epub 2005 Dec 20.
Peptide YY (PYY) has been implicated in the control of food intake through functional studies in rodents and humans. To investigate whether genetic alterations within this gene result in abnormal weight in humans, we sequenced its coding exons and splice sites in a large cohort of extremely obese [n = 379; average body mass index (BMI), 49.0 kg/m2] and lean (n = 378; average BMI, 19.5 kg/m2) individuals. In total, three rare non-synonymous variants were identified, only one of which, PYY Q62P, exhibited familial segregation with body mass. Through serendipity, previous studies based on cell culture revealed this precise variant to have altered receptor-binding selectivity in vitro. We further show, using mouse peptide injection experiments, that while the wild-type PYY peptide reduces food intake, the mutant PYY 62P had an insignificant effect in reducing food intake in vivo. Taken together, these results are the first to support that rare sequence variants within PYY can influence human susceptibility to obesity.
通过在啮齿动物和人类中的功能研究，发现肽YY（PYY）与食物摄入的控制有关。为了研究该基因内的基因改变是否会导致人类体重异常，我们对一大群极度肥胖者（n = 379；平均体重指数[BMI]，49.0kg/m²）和瘦人（n = 378；平均BMI，19.5kg/m²）的编码外显子和剪接位点进行了测序。总共鉴定出三个罕见的非同义变体，其中只有一个，即PYY Q62P，与体重呈现家族性分离。巧合的是，先前基于细胞培养的研究表明，这个精确的变体在体外改变了受体结合选择性。我们进一步通过小鼠肽注射实验表明，虽然野生型PYY肽可减少食物摄入，但突变型PYY 62P在体内减少食物摄入的作用不显著。综上所述，这些结果首次支持PYY内的罕见序列变体可影响人类肥胖易感性。
