Arachidonic acid stimulates glucose uptake in 3T3-L1 adipocytes by increasing GLUT1 and GLUT4 levels at the plasma membrane - Evidence for involvement of lipoxygenase metabolites and peroxisome proliferator-activated receptor gamma
C. Nugent et al., Arachidonic acid stimulates glucose uptake in 3T3-L1 adipocytes by increasing GLUT1 and GLUT4 levels at the plasma membrane - Evidence for involvement of lipoxygenase metabolites and peroxisome proliferator-activated receptor gamma, J BIOL CHEM, 276(12), 2001, pp. 9149-9157
Exposure of insulin-sensitive tissues to free fatty acids can impair glucos
e disposal through inhibition of carbohydrate oxidation and glucose transpo
rt. However, certain fatty acids and their derivatives can also act as endo
genous ligands for peroxisome proliferator-activated receptor gamma (PPAR g
amma), a nuclear receptor that positively modulates insulin sensitivity. To
clarify the effects of externally delivered fatty acids on glucose uptake
in an insulin-responsive cell type, we systematically examined the effects
of a range of fatty acids on glucose uptake in 3T3-L1 adipocytes. Of the fa
tty acids examined, arachidonic acid (AA) had the greatest positive effects
, significantly increasing basal and insulin-stimulated glucose uptake by 1
.8- and 2-fold, respectively, with effects being maximal at 4 h at which ti
me membrane phospholipid content of AA was markedly increased. The effects
of AA were sensitive to the inhibition of protein synthesis but were unrela
ted to changes in membrane fluidity. AA had no effect on total cellular lev
els of glucose transporters, but significantly increased levels of GLUT1 an
d GLUT4 at the plasma membrane. While the effects of AA were insensitive to
cyclooxygenase inhibition, the lipoxygenase inhibitor, nordihydroguaiareti
c acid, substantially blocked the AA effect on basal glucose uptake. Furthe
rmore, adenoviral expression of a dominant-negative PPAR gamma mutant atten
uated the AA potentiation of basal glucose uptake. Thus, AA potentiates bas
al and insulin-stimulated glucose uptake in 3T3-L1 adipocytes by a cyclooxy
genase-independent mechanism that increases the levels of both GLUT1 and GL
UT4 at the plasma membrane. These effects are at least partly dependent on
de novo protein synthesis, an intact lipoxygenase pathway and the activatio
n of PPAR gamma with these pathways having a greater role in the absence th
an in the presence of insulin.