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Upregulation of Tribbles decreases body weight and increases sleep duration.

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Published version
Peer-reviewed

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Abstract

Eukaryotic Tribbles proteins are pseudoenzymes that regulate multiple aspects of intracellular signalling. Both Drosophila melanogaster and mammalian members of this family of pseudokinases act as negative regulators of insulin signalling. Mammalian tribbles pseudokinase (TRIB) genes have also been linked to insulin resistance and type 2 diabetes mellitus. Type 2 diabetes mellitus is associated with increased body weight, sleep problems and increased long-term mortality. Here, we investigated how manipulating the expression of Tribbles impacts body weight, sleep and mortality. We showed that the overexpression of Drosophila tribbles (trbl) in the fly fat body reduces both body weight and lifespan in adult flies without affecting food intake. Furthermore, it decreases the levels of Drosophila insulin-like peptide 2 (DILP2; ILP2) and increases night-time sleep. The three genes encoding TRIBs of mammals, TRIB1, TRIB2 and TRIB3, show both common and unique features. As the three human TRIB genes share features with Drosophila trbl, we further explored the links between TRIB genetic variants and both body weight and sleep in the human population. We identified associations between the polymorphisms and expression levels of the pseudokinases and markers of body weight and sleep duration. We conclude that Tribbles pseudokinases are involved in the control of body weight, lifespan and sleep.

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Peer reviewed: True


Acknowledgements: We thank the Vienna Drosophila RNAi Center, Bloomington Drosophila Stock Center, L. Dobens and A. Telemans for providing the fly stocks, and the Fly Facility, Department of Genetics, University of Cambridge, for supplying fly food and generating transgenic lines.


Funder: University of Cambridge; Id: http://dx.doi.org/10.13039/501100000735

Keywords

Drosophila, Fat body, Lifespan, Lipid metabolism, Sleep, Tribbles, Animals, Humans, Body Weight, Calcium-Calmodulin-Dependent Protein Kinases, Cell Cycle Proteins, Diabetes Mellitus, Type 2, Drosophila melanogaster, Insulin, Intracellular Signaling Peptides and Proteins, Mammals, Neuropeptides, Protein Serine-Threonine Kinases, Sleep Duration, Up-Regulation

Journal Title

Dis Model Mech

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Journal ISSN

1754-8403
1754-8411

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Publisher

The Company of Biologists
Sponsorship
Medical Research Council (MC_UU_00025/3)