RRC ID 68674
Author Agrawal N, Lawler K, Davidson CM, Keogh JM, Legg R, INTERVAL, Barroso I, Farooqi IS, Brand AH.
Title Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.
Journal PLoS Biol
Abstract 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.
Volume 19(11)
Pages e3001255
Published 2021-11-1
DOI 10.1371/journal.pbio.3001255
PMID 34748544
PMC PMC8575313
MeSH Age of Onset Animals Case-Control Studies Drosophila Proteins / genetics Drosophila Proteins / metabolism Drosophila melanogaster / genetics* Female Genetic Association Studies* Genetic Testing* Homozygote Humans Male Mutation / genetics Obesity / genetics* Pedigree Signal Transduction / genetics
IF 7.076
Drosophila 1063R-2