The evolutionarily conserved
kinase PIKfyve that synthesizes
PtdIns5P and
PtdIns(3,5)P₂ has been implicated in
insulin-regulated GLUT4 translocation/
glucose entry in 3T3-L1 adipocytes. To decipher PIKfyve's role in muscle and systemic
glucose metabolism, here we have developed a novel mouse model with Pikfyve gene disruption in striated muscle (MPIfKO). These mice exhibited systemic
glucose intolerance and
insulin resistance at an early age but had unaltered muscle mass or proportion of slow/fast-twitch muscle fibers.
Insulin stimulation of in vivo or ex vivo
glucose uptake and GLUT4 surface translocation was severely blunted in skeletal muscle. These changes were associated with premature attenuation of Akt phosphorylation in response to in vivo
insulin, as tested in young mice. Starting
at 10-11 wk of age, MPIfKO mice progressively accumulated greater
body weight and fat mass. Despite increased adiposity, serum
free fatty acid and
triglyceride levels were normal until adulthood. Together with the undetectable
lipid accumulation in liver, these data suggest that lipotoxicity and muscle fiber switching do not contribute to muscle
insulin resistance in MPIfKO mice. Furthermore, the 80% increase in total fat mass resulted from increased fat cell size rather than altered fat cell number. The observed profound
hyperinsulinemia combined with the documented increases in constitutive Akt activation, in vivo
glucose uptake, and gene expression of key
enzymes for
fatty acid biosynthesis in MPIfKO fat tissue suggest that the latter is being sensitized for de novo
lipid anabolism. Our data provide the first in vivo evidence that PIKfyve is essential for systemic
glucose homeostasis and
insulin-regulated
glucose uptake/GLUT4 translocation in skeletal muscle.