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


Change log
Authors
Lawler, Katherine 
Davidson, Catherine  ORCID logo  https://orcid.org/0000-0002-4784-1398
Keogh, Julia M 
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.

Description

Funder: Royal Society Darwin Trust Research Professorship


Funder: NIHR Cambridge Biomedical Research Centre


Funder: NIHR Senior Investigator Award


Funder: NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust


Funder: Higher Education Funding Council for England Catalyst


Funder: Health Data Research UK


Funder: NHS National Institute for Health Research Clinical Research Network (North Thames)


Funder: Bernard Wolfe Health Neuroscience Endowment


Funder: The Botnar Fondation

Keywords
Short Reports, Biology and life sciences, Research and analysis methods, Medicine and health sciences
Journal Title
PLoS Biol
Conference Name
Journal ISSN
1544-9173
1545-7885
Volume Title
19
Publisher
Public Library of Science (PLoS)
Sponsorship
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
Wellcome Trust (103792/Z/14/Z)
Wellcome Trust (207462/Z/17/Z)
Wellcome Trust (208363/Z/17/Z)
British Heart Foundation (RG/18/13/33946)