The goal of this study is to understand the function and regulatory mechanism of TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) in skeletal muscle glucose metabolism. TBC1D1 has been identified as an obesity candidate gene in humans that potentially regulates GLUT4 translocation in adipocytes. TBC1D1 is an Akt-substrate 160 (AS160) paralog that is highly expressed in skeletal muscle and is responsive to insulin-, contraction-, and the AMP-activated protein kinase (AMPK) activator AICARstimulation. TBC1D1 may be a critical determinant of fuel homeostasis, yet nothing is known about the regulation and function of this protein in skeletal muscle. The systematic investigation of TBC1D1 could provide the rationale for development of novel therapeutic interventions for the treatment of diabetes. Exercise, i.e. contraction, leads to increased glucose uptake by skeletal muscle through a complex series of signaling events, including AS160 phosphorylation. Contraction also causes an increase in TBC1D1 phosphorylation. We hypothesize that TBC1D1 plays a critical role in skeletal muscle metabolism and is a nexus for convergent signaling by multiple stimuli that increase glucose uptake in muscle.
My first aim will examine the upstream regulation of TBC1D1 in contraction- and insulin-stimulated skeletal muscle. To test the hypotheses for this aim, I plan to use a gene transfer system, immunoblotting, and existing transgenic mouse models.
My second aim will examine TBC1D1 function in skeletal muscle metabolism. To investigate this aim I will continue to use a gene transfer system, immunoblotting and transgenic mouse models;in addition to a radioactive glucose transport assay.
This research will add to our understanding of skeletal muscle glucose metabolism and potentially identify novel targets for future development of therapeutic diabetes interventions.
