PPARalpha /gamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly

• Published in: American journal of physiology: endocrinology and metabolism Vol. 284; no. 3; p. E531
• Main Authors: Ye, Ji-Ming, Iglesias, Miguel A, Watson, David G, Ellis, Bronwyn, Wood, Leonie, Jensen, Per Bo, Sorensen, Rikke Veggerby, Larsen, Philip Just, Cooney, Gregory J, Wassermann, Karsten, Kraegen, Edward W
• Format: Journal Article
• Language: English
• Published: United States 01.03.2003
• Subjects: Animals; Dietary Fats - administration & dosage; Dietary Fats - adverse effects; Fatty Liver - drug therapy; Fatty Liver - etiology; Fatty Liver - physiopathology; Glucose - metabolism; Glucose Clamp Technique; Insulin - metabolism; Insulin Resistance; Lipid Metabolism; Liver - metabolism; Male; Muscle, Skeletal - metabolism; Oxazines - therapeutic use; Phenylpropionates - therapeutic use; Pyrimidines - therapeutic use; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear - agonists; Thiazoles - therapeutic use; Thiazolidinediones; Transcription Factors - agonists
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00299.2002

1  Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia; 2  Rheoscience, DK-2100 Copenhagen; and 3  Novo Nordisk, DK-2760 Måløv, Denmark Peroxisome proliferator-activated receptor (PPAR) and PPAR 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 PPAR / agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPAR agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPAR 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 PPAR / agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPAR ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPAR activation, but without hepatomegaly. peroxisome proliferator-activated receptor subtypes; adipokines; tissue lipids; insulin resistance