We examined the effects of activation of
peroxisome proliferator-activated receptor (
PPAR)alpha,
PPARgamma, and both of them in combination in obese diabetic KKAy mice and investigated the mechanisms by which they improve
insulin sensitivity.
PPARalpha activation by its agonist,
Wy-14,643, as well as
PPARgamma activation by its agonist,
rosiglitazone, markedly improved
insulin sensitivity. Interestingly, dual activation of
PPARalpha and -gamma by a combination of
Wy-14,643 and
rosiglitazone showed increased efficacy. Adipocyte size in Wy-14,643-treated KKAy mice was much smaller than that of vehicle- or
rosiglitazone-treated mice, suggesting that activation of
PPARalpha prevents adipocyte
hypertrophy. Moreover,
Wy-14,643 treatment reduced
inflammation and the expression of macrophage-specific genes in white adipose tissue (WAT). Importantly,
Wy-14,643 treatment upregulated expression of the
adiponectin receptor (AdipoR)-1 and AdipoR2 in WAT, which was decreased in WAT of KKAy mice compared with that in nondiabetic control mice. Furthermore,
Wy-14,643 directly increased expression of AdipoRs and decreased
monocyte chemoattractant protein-1 expression in adipocytes and macrophages.
Rosiglitazone increased serum
adiponectin concentrations and the ratio of high molecular weight multimers of
adiponectin to total
adiponectin. A combination of
rosiglitazone and
Wy-14,643 increased both serum
adiponectin concentrations and AdipoR expression in WAT. These data suggest that
PPARalpha activation prevents
inflammation in WAT and that dual activation of
PPARalpha and -gamma enhances the action of
adiponectin by increasing both
adiponectin and AdipoRs, which can result in the amelioration of
obesity-induced
insulin resistance.