Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila

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 candi...

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Autores principales: Neha Agrawal, Katherine Lawler, Catherine M. Davidson, Julia M. Keogh, Robert Legg, INTERVAL, Inês Barroso, I. Sadaf Farooqi, Andrea H. Brand
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Publicado: Public Library of Science (PLoS) 2021
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spelling oai:doaj.org-article:79111040580e450d8f11ece9a93f657d2021-11-18T05:34:49ZPredicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila1544-91731545-7885https://doaj.org/article/79111040580e450d8f11ece9a93f657d2021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575313/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885The 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.Neha AgrawalKatherine LawlerCatherine M. DavidsonJulia M. KeoghRobert LeggINTERVALInês BarrosoI. Sadaf FarooqiAndrea H. BrandPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 11 (2021)
institution DOAJ
collection DOAJ
language EN
topic Biology (General)
QH301-705.5
spellingShingle Biology (General)
QH301-705.5
Neha Agrawal
Katherine Lawler
Catherine M. Davidson
Julia M. Keogh
Robert Legg
INTERVAL
Inês Barroso
I. Sadaf Farooqi
Andrea H. Brand
Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila
description 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.
format article
author Neha Agrawal
Katherine Lawler
Catherine M. Davidson
Julia M. Keogh
Robert Legg
INTERVAL
Inês Barroso
I. Sadaf Farooqi
Andrea H. Brand
author_facet Neha Agrawal
Katherine Lawler
Catherine M. Davidson
Julia M. Keogh
Robert Legg
INTERVAL
Inês Barroso
I. Sadaf Farooqi
Andrea H. Brand
author_sort Neha Agrawal
title Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila
title_short Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila
title_full Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila
title_fullStr Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila
title_full_unstemmed Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila
title_sort predicting novel candidate human obesity genes and their site of action by systematic functional screening in drosophila
publisher Public Library of Science (PLoS)
publishDate 2021
url https://doaj.org/article/79111040580e450d8f11ece9a93f657d
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