Objective

More than 300 genetic variants have been robustly associated with measures of human adiposity. Highly penetrant mutations causing human obesity do so largely by disrupting satiety pathways in the brain and increasing food intake. Most of the common obesity-predisposing variants are in, or near, genes that are expressed highly in the brain, but little is known about their function. Exploring the biology of these genes at scale in mammalian systems is challenging. We sought to establish and validate the use of a multicomponent screen for feeding behaviour phenotypes taking advantage of the tractable model organism Drosophila melanogaster.

Methods

We validated a screen for feeding behaviour in Drosophila by comparing results after disrupting expression of centrally-expressed genes that influence energy balance in flies to those of ten control genes. We then used this screen to explore the effects of disrupted expression of genes that are either a) implicated in energy homeostasis through human genome wide association studies (GWAS) or b) expressed and nutritionally responsive in specific populations of hypothalamic neurons with a known role in feeding/fasting.

Results

Using data from the validation study to classify responses, we studied 53 Drosophila orthologues of genes implicated by human GWAS in body mass index (BMI) and found that 15 significantly influenced feeding behaviour or energy homeostasis in the Drosophila screen. We then studied 50 Drosophila homologues of 47 murine genes that are reciprocally nutritionally regulated in POMC and AgRP neurons. Seven of these 50 genes were found by our screen to influence feeding behaviour in flies.

Conclusion

Here, we demonstrate the utility of Drosophila as a tractable model organism in a high-throughput genetic screen for food intake phenotypes. This simple and cost-efficient strategy is ideal for high-throughput interrogation of genes implicated in feeding behaviour and obesity in mammals, and will facilitate the process of reaching a functional understanding of obesity pathogenesis.

中文翻译：

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对果蝇摄食行为和营养状况进行多成分筛选，以询问哺乳动物食欲相关基因

 客观的

超过 300 种遗传变异与人类肥胖指标密切相关。导致人类肥胖的高度渗透性突变很大程度上是通过破坏大脑的饱腹感通路和增加食物摄入量来实现的。大多数常见的肥胖易感变异位于或接近大脑中高表达的基因，但对其功能知之甚少。在哺乳动物系统中大规模探索这些基因的生物学具有挑战性。我们试图利用易驯化的模式生物果蝇来建立和验证多成分筛选的摄食行为表型的使用。

 方法

我们通过比较破坏影响果蝇能量平衡的中心表达基因与十个对照基因的表达后的结果，验证了果蝇摄食行为的筛选。然后，我们使用此筛选来探索基因表达中断的影响，这些基因要么a）通过人类全基因组关联研究（GWAS）与能量稳态有关，要么b）在特定的下丘脑神经元群体中表达并具有营养反应性，其已知的作用喂养/禁食。

 结果

我们利用验证研究的数据对反应进行分类，研究了与人类 GWAS 体重指数 (BMI) 相关的 53 个果蝇直系同源基因，发现其中 15 个显着影响果蝇筛选中的摄食行为或能量稳态。然后，我们研究了 47 个小鼠基因的 50 个果蝇同源物，这些基因在 POMC 和 AgRP 神经元中相互营养调节。我们的筛选发现这 50 个基因中有 7 个会影响果蝇的摄食行为。

 结论

在这里，我们展示了果蝇作为一种易处理的模型生物在食物摄入表型的高通量遗传筛选中的效用。这种简单且具有成本效益的策略非常适合高通量询问与哺乳动物摄食行为和肥胖有关的基因，并将促进对肥胖发病机制的功能性理解。