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

by Neha Agrawal, Katherine Lawler, Catherine M. Davidson, Julia M. Keogh, Robert Legg, INTERVAL , In ês Barroso, I. Sadaf Farooqi, Andrea H. Brand 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 can didate 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 inDrosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr,dachsous,calpA, andsdk). 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 inTAOK2 associated with human obesity. Knockdown ofDrosophila 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.
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research