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PPARα/γ ragaglitazer eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly


Ye, JM and Iglesias, MA and Watson, DG and Ellis, B and Wood, L and Jensen, PB and Sorensen, RV and Larsen, PJ and Cooney, GJ and Wassermann, K and Kraegen, EW, PPARα/γ ragaglitazer eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly, American Journal of Physiology: Endocrinology and Metabolism, 284, (3) pp. E531-540. ISSN 0193-1849 (2003) [Refereed Article]

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Copyright 2003 the American Physiological Society

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DOI: doi:10.1152/ajpendo.00299.2002


Peroxisome proliferator-activated receptor (PPAR)α and PPARγ 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 PPARα/γ agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPARα agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPARγ 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 PPARα/γ agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPARγ ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPARα activation, but without hepatomegaly.

Item Details

Item Type:Refereed Article
Keywords:peroxisome proliferator-activated receptor subtypes, adipokines, tissue lipids, insulin resistance
Research Division:Biomedical and Clinical Sciences
Research Group:Medical biochemistry and metabolomics
Research Field:Metabolic medicine
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Iglesias, MA (Dr Miguel Iglesias)
ID Code:80265
Year Published:2003
Web of Science® Times Cited:128
Deposited By:Health Sciences A
Deposited On:2012-10-25
Last Modified:2013-06-26

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