A novel
peroxisome proliferator-activated receptor (
PPAR) modulator, Z-551, having both PPARα agonistic and PPARγ antagonistic activities, has been developed for the treatment of
obesity and
obesity-related metabolic disorders. We examined the effects of Z-551 on
obesity and the metabolic disorders in wild-type mice on the high-fat diet (HFD). In mice on the HFD, Z-551 significantly suppressed
body weight gain and ameliorated
insulin resistance and abnormal
glucose and
lipid metabolisms. Z-551 inhibited visceral fat mass gain and adipocyte
hypertrophy, and reduced molecules involved in
fatty acid uptake and synthesis, macrophage infiltration, and
inflammation in adipose tissue. Z-551 increased molecules involved in
fatty acid combustion, while reduced molecules associated with gluconeogenesis in the liver. Furthermore, Z-551 significantly reduced fasting plasma levels of
glucose,
triglyceride,
free fatty acid,
insulin, and
leptin. To elucidate the significance of the
PPAR combination, we examined the effects of Z-551 in PPARα-deficient mice and those of a synthetic PPARγ antagonist in wild-type mice on the HFD. Both drugs showed similar, but weaker effects on
body weight,
insulin resistance and specific events provoked in adipose tissue compared with those of Z-551 as described above, except for lack of effects on fasting plasma
triglyceride and
free fatty acid levels. These findings suggest that Z-551 ameliorates HFD-induced
obesity,
insulin resistance, and impairment of
glucose and
lipid metabolisms by PPARα agonistic and PPARγ antagonistic activities, and therefore, might be clinically useful for preventing or treating
obesity and
obesity-related metabolic disorders such as
insulin resistance,
type 2 diabetes, and
dyslipidemia.