The obesity gene, TMEM18, is of ancient origin, found in majority of neuronal cells in all major brain regions and associated with obesity in severely obese children.
The obesity gene, TMEM18, is of ancient origin, found in majority of neuronal cells in all major brain regions and associated with obesity in severely obese children.
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DOI：
10.1186/1471-2350-11-58
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发表时间：
2010-04-09
影响因子：
--
通讯作者：
Schiöth HB
中科院分区：
文献类型：
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作者：
Almén MS;Jacobsson JA;Shaik JH;Olszewski PK;Cedernaes J;Alsiö J;Sreedharan S;Levine AS;Fredriksson R;Marcus C;Schiöth HB
TMEM18 是一种下丘脑基因，最近在全基因组关联研究中将其与肥胖和 BMI 联系起来。然而，TMEM18 的功能特性尚不清楚。利用系统发育和生物信息学方法推断了TMEM18的进化史。通过实时 PCR 在一组大鼠和小鼠组织中以及在小鼠大脑中通过免疫组织化学研究了该基因的表达谱。此外，还分析了三种与喂养相关的小鼠模型的基因表达变化：食物剥夺、奖励和饮食诱导的体重增加。最后，我们对 502 名严重肥胖儿童和 527 名健康瑞典儿童进行了 TMEM18 附近两个 SNP（rs6548238 和 rs756131）的基因分型。人们发现 TMEM18 非常保守，并且存在于 15 亿多年前脱离人类谱系的物种中。 TMEM18 基因在所有主要大脑区域的大多数细胞中广泛表达和检测，但在神经元中比其他细胞类型更丰富。我们发现在进食相关的小鼠模型中下丘脑和脑干表达没有显着变化。 TMEM18 位点的两个 SNP（rs6548238 和 rs756131）与肥胖风险增加有很强的相关性（p = 0.001 和 p = 0.002）。我们得出结论，TMEM18 与成人和儿童肥胖有关。它是最保守的人类肥胖基因之一，存在于大多数大脑部位，包括下丘脑和脑干，但在经典能量稳态模型中，这些区域不受其调节。
TMEM18 is a hypothalamic gene that has recently been linked to obesity and BMI in genome wide association studies. However, the functional properties of TMEM18 are obscure. The evolutionary history of TMEM18 was inferred using phylogenetic and bioinformatic methods. The gene's expression profile was investigated with real-time PCR in a panel of rat and mouse tissues and with immunohistochemistry in the mouse brain. Also, gene expression changes were analyzed in three feeding-related mouse models: food deprivation, reward and diet-induced increase in body weight. Finally, we genotyped 502 severely obese and 527 healthy Swedish children for two SNPs near TMEM18 (rs6548238 and rs756131). TMEM18 was found to be remarkably conserved and present in species that diverged from the human lineage over 1500 million years ago. The TMEM18 gene was widely expressed and detected in the majority of cells in all major brain regions, but was more abundant in neurons than other cell types. We found no significant changes in the hypothalamic and brainstem expression in the feeding-related mouse models. There was a strong association for two SNPs (rs6548238 and rs756131) of the TMEM18 locus with an increased risk for obesity (p = 0.001 and p = 0.002). We conclude that TMEM18 is involved in both adult and childhood obesity. It is one of the most conserved human obesity genes and it is found in the majority of all brain sites, including the hypothalamus and the brain stem, but it is not regulated in these regions in classical energy homeostatic models.