Abstract
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.
Highlights
Obesity is one of the principal causes of metabolic syndrome
Z-551 Is a Novel peroxisome proliferator-activated receptor (PPAR) Modulator Having Both PPAR␣ Agonistic and PPAR␥ Antagonistic Activities—Agonistic and antagonistic activities of Z-551 for each PPAR were quantitatively determined by the luciferase reporter assay
We investigated the preventive and therapeutic effects of Z-551 using WT mice and wild-type diet-induced obese (WT DIO) mice on the high-fat diet (HFD) to elucidate the mechanisms of Z-551 actions, and thereby examining its potential of being a clinically useful drug for diet-induced obesity and obesity-related metabolic disorders such as insulin resistance, type 2 diabetes, dyslipidemia, and fatty liver diseases
Summary
Obesity is one of the principal causes of metabolic syndrome. Results: A novel PPAR␣ agonist/␥ antagonist, Z-551, ameliorates obesity, insulin resistance, and impairment of glucose and lipid metabolisms in mice. To elucidate the significance of the PPAR combination, we examined the effects of Z-551 in PPAR␣-deficient mice and those of a synthetic PPAR␥ 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. 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 PPAR␣ agonistic and PPAR␥ antagonistic activities, and might be clinically useful for preventing or treating obesity
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