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Towards this end, genome-wide association studies (GWAS) have identified hundreds of human genetic variants associated with obesity. The next challenge is to experimentally define which of these variants are causally linked to obesity, and could therefore become targets for the treatment or prevention of obesity. Here we employ high-throughput<jats:italic>in vivo<\/jats:italic>RNAi screening to test for causality 293<jats:italic>C<\/jats:italic>.<jats:italic>elegans<\/jats:italic>orthologs of human obesity-candidate genes reported in GWAS. We RNAi screened these 293 genes in<jats:italic>C<\/jats:italic>.<jats:italic>elegans<\/jats:italic>subject to two different feeding regimens: (1) regular diet, and (2) high-fructose diet, which we developed and present here as an invertebrate model of diet-induced obesity (DIO). We report 14 genes that promote obesity and 3 genes that prevent DIO when silenced in<jats:italic>C<\/jats:italic>.<jats:italic>elegans<\/jats:italic>. Further, we show that knock-down of the 3 DIO genes not only prevents excessive fat accumulation in primary and ectopic fat depots but also improves the health and extends the lifespan of<jats:italic>C<\/jats:italic>.<jats:italic>elegans<\/jats:italic>overconsuming fructose. Importantly, the direction of the association between expression variants in these loci and obesity in mice and humans matches the phenotypic outcome of the loss-of-function of the<jats:italic>C<\/jats:italic>.<jats:italic>elegans<\/jats:italic>ortholog genes, supporting the notion that some of these genes would be causally linked to obesity across phylogeny. Therefore, in addition to defining causality for several genes so far merely correlated with obesity, this study demonstrates the value of model systems compatible with<jats:italic>in vivo<\/jats:italic>high-throughput genetic screening to causally link GWAS gene candidates to human diseases.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009736","type":"journal-article","created":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T17:56:04Z","timestamp":1631037364000},"page":"e1009736","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":32,"title":["Genes in human obesity loci are causal obesity genes in C. 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