Peroxisome proliferator-activated receptor (
PPAR)alpha and
PPARgamma agonists lower
lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on
insulin sensitivity and lipid metabolism by the dual
PPARalpha/gamma agonist
ragaglitazar in high fat-fed rats.
Ragaglitazar completely eliminated high-fat feeding-induced liver
triglyceride accumulation and visceral adiposity, like the
PPARalpha agonist
Wy-14643 but without causing
hepatomegaly. In contrast, the
PPARgamma agonist
rosiglitazone only slightly lessened liver
triglyceride without affecting visceral adiposity. Compared with
rosiglitazone or
Wy-14643,
ragaglitazar showed a much greater effect (79%, P < 0.05) to enhance
insulin's suppression of hepatic
glucose output. Whereas all three
PPAR agonists lowered plasma
triglyceride levels and lessened muscle long-chain acyl-CoAs,
ragaglitazar and
rosiglitazone had greater
insulin-sensitizing action in muscle than
Wy-14643, associated with a threefold increase in plasma
adiponectin levels. There was a significant correlation of
lipid content and
insulin action in liver and particularly muscle with
adiponectin levels (P < 0.01). We conclude that the
PPARalpha/gamma agonist
ragaglitazar has a therapeutic potential for
insulin-resistant states as a
PPARgamma ligand, with possible involvement of
adiponectin. Additionally, it can counteract
fatty liver, hepatic
insulin resistance, and visceral adiposity generally associated with
PPARalpha activation, but without
hepatomegaly.