The pseudokinase TRB3 disrupts insulin signaling by binding to and inhibiting the Ser/Thr kinase AKT. Amounts of TRB3 protein are elevated in liver and adipose during fasting;but the role of TRB3 in maintaining energy balance under these conditions remains unclear. In recent studies, we found that TRB3 promotes fatty acid oxidation in adipose by associating with acetyl coA carboxylase (ACC), the rate limiting enzyme in fatty acid synthesis. TRB3 inhibits ACC activity by mediating an interaction with the E3 ubiquitin ligase COP1, which in turn ubiquitinates ACC. This proposal investigates the role of TRB3 in modulating insulin signaling and fatty acid oxidation pathways in adipose and muscle.
Three specific aims are proposed: 1. We will test the potential role of TRB3 as an adaptor for the E3 ubiquitin ligase COP1 in adipocytes. Specifically, we will test whether TRB3 mediates an interaction between COP1 and Acetyl coA carboxylase (ACC) during fasting. We will identify ubiquitination sites in ACC, and we will test the relative effects of ubiquitination on ACC catalytic activity and protein stability. The effect of COP1 on the interaction of TRB3 with AKT and other TRB3-associated proteins will be tested. 2. We will test the relative effects of TRB3 on insulin signaling and fatty acid oxidation in adipose by characterizing transgenic mice expressing wild-type TRB3 as well as COP1- or AKT-interaction defective TRB3 polypeptides from the adipose-specific aP2 promoter. 3. We will characterize the role of TRB3 in regulating glucose and fatty acid oxidation in skeletal muscle. In particular, we will evaluate the mechanism by which TRB3 is expressed in oxidative but not glycolytic fibers, focusing on the potential involvement of the nuclear hormone receptor PPAR delta and the coactivator PGC1a in this process. The importance of TRB3 in promoting fatty acid oxidation and blocking glucose uptake in oxidative but not glycolytic skeletal muscle fibers will also be determined using transgenic mice expressing wild-type, AKT- and COP1- interaction defective TRB3 proteins in skeletal muscle. Insulin resistance is a hallmark in the development of type II diabetes, which is characterized by alterations in both glucose and lipid metabolism. The proposed studies will provide insight into the role of TRB3 in this process. During feeding, the body delivers glucose, a critical fuel, to our muscles, by releasing insulin from the pancreas. This process is disrupted in adult-onset diabetes, largely because the insulin signal can't be 'heard'by the muscle, for reasons that are still unclear. The current proposal focuses on the role of a so- called insulin resistance protein called TRB3 in preventing the insulin signal from working in muscle and other tissues in the body.
|Altarejos, Judith Y; Montminy, Marc (2011) CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol 12:141-51|
|Wang, Yiguo; Vera, Liliana; Fischer, Wolfgang H et al. (2009) The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature 460:534-7|
|Qi, Ling; Heredia, Jose E; Altarejos, Judith Y et al. (2006) TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science 312:1763-6|