Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.
Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.
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DOI：
10.1371/journal.pbio.3001255
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发表时间：
2021-11
期刊：
影响因子：
9.8
通讯作者：
Brand AH
中科院分区：
文献类型：
--
作者：
Agrawal N;Lawler K;Davidson CM;Keogh JM;Legg R;INTERVAL;Barroso I;Farooqi IS;Brand AH
人类肥胖相关基因的发现可以揭示减肥治疗的新机制。对肥胖个体的遗传研究和对罕见遗传变异的分析可以识别新的肥胖相关基因。然而，建立这些候选基因和肥胖之间的功能关系仍然是一个重大的挑战。我们通过对严重肥胖儿童（包括来自近亲家庭的儿童）进行外显子组测序，发现了大量罕见的纯合基因变异。通过评估这些基因在果蝇体内的功能，我们确定了4个基因，以前没有与人类肥胖，调节肥胖（itpr，dachsous，calpA和sdk）。Dachsous是Hippo信号通路上游的跨膜蛋白。我们发现，Hippo通路的另外3个成员，脂肪，四关节和河马，也调节肥胖，它们作用于神经元，而不是脂肪组织（脂肪体）。在较大的人类队列中筛选Hippo通路基因，发现TAOK2中与人类肥胖相关的罕见变异。敲除果蝇tao增加了体内肥胖，证明了我们的方法在预测新的人类肥胖基因和信号通路及其作用位点方面的优势。本研究旨在通过将人类外泌体测序分析与果蝇中的系统功能筛选相结合，确定可能导致人类肥胖的新基因变体。这确定了一些新的肥胖相关基因，这些基因控制苍蝇的肥胖，并揭示了Hippo信号通路在肥胖中的潜在作用。
The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action. This study set out to identify novel gene variants that may contribute to human obesity, by combining human exosome sequencing analyses with systematic functional screening in Drosophila. This identifies a number of novel obesity-associated genes which control adiposity in flies, and uncovers a potential role for the Hippo signaling pathway in obesity.
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DOI：
10.1073/pnas.0702726104
发表时间：
2007-05-15
影响因子：
11.1
作者：
Ja, William W.;Carvalho, Gil B.;Benzer, Seymour
通讯作者：
Benzer, Seymour
DOI：
10.1016/s0140-6736(17)31928-1
发表时间：
2017-11-25
期刊：
Lancet (London, England)
影响因子：
--
作者：
Di Angelantonio E;Thompson SG;Kaptoge S;Moore C;Walker M;Armitage J;Ouwehand WH;Roberts DJ;Danesh J;INTERVAL Trial Group
通讯作者：
INTERVAL Trial Group
影响因子：
4.5
作者：
Baranski TJ;Kraja AT;Fink JL;Feitosa M;Lenzini PA;Borecki IB;Liu CT;Cupples LA;North KE;Province MA
通讯作者：
Province MA
影响因子：
16.2
作者：
Al-Anzi, Bader;Sapin, Viveca;Waters, Christopher;Zinn, Kai;Wyman, Robert J.;Benzer, Seymour
通讯作者：
Benzer, Seymour
影响因子：
9.8
作者：
Finegan, Tara M.;Hervieux, Nathan;Sanson, Benedicte
通讯作者：
Sanson, Benedicte