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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575313/ https://www.ncbi.nlm.nih.gov/pubmed/34748544 http://dx.doi.org/10.1371/journal.pbio.3001255 |
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author | Agrawal, Neha Lawler, Katherine Davidson, Catherine M. Keogh, Julia M. Legg, Robert Barroso, Inês Farooqi, I. Sadaf Brand, Andrea H. |
author_facet | Agrawal, Neha Lawler, Katherine Davidson, Catherine M. Keogh, Julia M. Legg, Robert Barroso, Inês Farooqi, I. Sadaf Brand, Andrea H. |
author_sort | Agrawal, Neha |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-8575313 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-85753132021-11-09 Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila Agrawal, Neha Lawler, Katherine Davidson, Catherine M. Keogh, Julia M. Legg, Robert Barroso, Inês Farooqi, I. Sadaf Brand, Andrea H. PLoS Biol Short Reports 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. Public Library of Science 2021-11-08 /pmc/articles/PMC8575313/ /pubmed/34748544 http://dx.doi.org/10.1371/journal.pbio.3001255 Text en © 2021 Agrawal et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Short Reports Agrawal, Neha Lawler, Katherine Davidson, Catherine M. Keogh, Julia M. Legg, Robert Barroso, Inês Farooqi, I. Sadaf Brand, Andrea H. Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila |
title | 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_short | 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 |
topic | Short Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575313/ https://www.ncbi.nlm.nih.gov/pubmed/34748544 http://dx.doi.org/10.1371/journal.pbio.3001255 |
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