The RabGAPs TBC1D1 and TBC1D4 control uptake of long-chain fatty acids into skeletal muscle via fatty acid transporter SLC27A4/FATP4 Short title: RabGAPs in skeletal muscle lipid metabolism

The two closely related RabGTPase-activating proteins (RabGAPs) TBC1D1 and TBC1D4 play a crucial role in the regulation of GLUT4 translocation in response to insulin and contraction in skeletal muscle. In mice, deficiency in one or both RabGAPs leads to reduced insulin and contraction-stimulated glucose uptake, and to elevated fatty acid uptake and oxidation in both glycolytic and oxidative muscle fibers without altering mitochondrial copy number and the abundance of OXPHOS proteins. Here we present evidence for a novel mechanism of skeletal muscle lipid utilization involving the two RabGAPs and the fatty acid transporter SLC27A4/FATP4. Both RabGAPs control the uptake of saturated and unsaturated long-chain fatty acids (LCFAs) into skeletal muscle and knockdown of a subset of RabGAP substrates, Rab8, Rab10 or Rab14, decreased LCFA uptake into these cells. In skeletal muscle from Tbc1d1/Tbc1d4 knockout animals, SLC27A4/FATP4 abundance was increased and depletion of SLC27A4/FATP4 but not FAT/CD36 completely abrogated the enhanced fatty acid oxidation in RabGAP-deficient skeletal muscle and cultivated C2C12 myotubes. Collectively, our data demonstrate that RabGAP-mediated control of skeletal muscle lipid metabolism converges with glucose metabolism at the level of downstream RabGTPases and involves regulated transport of LCFAs via SLC27A4/FATP4.