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, <i>Rab8,
Rab10 </i>or <i>Rab14, </i>decreased LCFA
uptake into these cells. In skeletal muscle from <i>Tbc1d1/Tbc1d4</i> 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.