Upregulation of Tribbles decreases body weight and increases sleep duration

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 (T2DM). T2DM is associated with body weight, sleep problems and increased long-term mortality. Here, we ask how manipulating the expression of Tribbles impacts body weight, sleep and mortality. We show that the overexpression of Drosophila tribbles (trbl) in the fly fat body reduces both the body weight and lifespan in adult flies without affecting food intake. Furthermore, it decreases the levels of Drosophila insulin-like peptide 2 (DILP2) and increases nighttime sleep. The 3 TRIB pseudokinases of mammals, TRIB1, TRIB2 and TRIB3, show both common and unique features. As the three human TRIB pseudokinases share features with Drosophila Trbl, we further explore the links between TRIB genetic variants and both body weight and sleep in the human population. We identify 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.