Genes in human obesity loci are causal obesity genes in C. elegans.

Obesity and its associated metabolic syndrome are a leading cause of morbidity and mortality. Given the disease's heavy burden on patients and the healthcare system, there has been increased interest in identifying pharmacological targets for the treatment and prevention of obesity. Towards thi...

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Autores principales:	Wenfan Ke, Jordan N Reed, Chenyu Yang, Noel Higgason, Leila Rayyan, Carolina Wählby, Anne E Carpenter, Mete Civelek, Eyleen J O'Rourke
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/ca9c57c357704cf4bc78b298a45d7a47
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spelling	oai:doaj.org-article:ca9c57c357704cf4bc78b298a45d7a472021-12-02T20:03:03ZGenes in human obesity loci are causal obesity genes in C. elegans.1553-73901553-740410.1371/journal.pgen.1009736https://doaj.org/article/ca9c57c357704cf4bc78b298a45d7a472021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009736https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Obesity and its associated metabolic syndrome are a leading cause of morbidity and mortality. Given the disease's heavy burden on patients and the healthcare system, there has been increased interest in identifying pharmacological targets for the treatment and prevention of obesity. 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 in vivo RNAi screening to test for causality 293 C. elegans orthologs of human obesity-candidate genes reported in GWAS. We RNAi screened these 293 genes in C. elegans 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 C. elegans. 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 C. elegans 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 C. elegans 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 in vivo high-throughput genetic screening to causally link GWAS gene candidates to human diseases.Wenfan KeJordan N ReedChenyu YangNoel HiggasonLeila RayyanCarolina WählbyAnne E CarpenterMete CivelekEyleen J O'RourkePublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 9, p e1009736 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Wenfan Ke Jordan N Reed Chenyu Yang Noel Higgason Leila Rayyan Carolina Wählby Anne E Carpenter Mete Civelek Eyleen J O'Rourke Genes in human obesity loci are causal obesity genes in C. elegans.
description	Obesity and its associated metabolic syndrome are a leading cause of morbidity and mortality. Given the disease's heavy burden on patients and the healthcare system, there has been increased interest in identifying pharmacological targets for the treatment and prevention of obesity. 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 in vivo RNAi screening to test for causality 293 C. elegans orthologs of human obesity-candidate genes reported in GWAS. We RNAi screened these 293 genes in C. elegans 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 C. elegans. 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 C. elegans 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 C. elegans 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 in vivo high-throughput genetic screening to causally link GWAS gene candidates to human diseases.
format	article
author	Wenfan Ke Jordan N Reed Chenyu Yang Noel Higgason Leila Rayyan Carolina Wählby Anne E Carpenter Mete Civelek Eyleen J O'Rourke
author_facet	Wenfan Ke Jordan N Reed Chenyu Yang Noel Higgason Leila Rayyan Carolina Wählby Anne E Carpenter Mete Civelek Eyleen J O'Rourke
author_sort	Wenfan Ke
title	Genes in human obesity loci are causal obesity genes in C. elegans.
title_short	Genes in human obesity loci are causal obesity genes in C. elegans.
title_full	Genes in human obesity loci are causal obesity genes in C. elegans.
title_fullStr	Genes in human obesity loci are causal obesity genes in C. elegans.
title_full_unstemmed	Genes in human obesity loci are causal obesity genes in C. elegans.
title_sort	genes in human obesity loci are causal obesity genes in c. elegans.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/ca9c57c357704cf4bc78b298a45d7a47
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_version_	1718375686175981568

Genes in human obesity loci are causal obesity genes in C. elegans.

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