| Title: | Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila |
| Journal: | PLOS Biology |
| Published: | 8 Nov 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34748544/ |
| DOI: | https://doi.org/10.1371/journal.pbio.3001255 |
| URL: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3001255&type=printable |
Publication 10587
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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.</p>
9 Authors
- Neha Agrawal
- Katherine Lawler
- Catherine M. Davidson
- Julia M. Keogh
- Robert Legg
- INTERVAL
- Inês Barroso
- I. Sadaf Farooqi
- Andrea H. Brand
1 Application
| Application ID | Title |
|---|---|
| 53821 | Genetic basis of body weight regulation in the population: comparison with extreme phenotypes of severe obesity and persistent thinness |
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