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Effects of cevoglitazar, a dual PPARα/γ agonist, on ectopic fat deposition in fatty Zucker rats
Author(s) -
Laurent D.,
Gounarides J. S.,
Gao J.,
Boettcher B. R.
Publication year - 2009
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2008.01017.x
Subject(s) - pioglitazone , fenofibrate , endocrinology , medicine , insulin resistance , chemistry , agonist , steatosis , peroxisome proliferator activated receptor , rosiglitazone , leptin , adipose tissue , lipid metabolism , insulin , type 2 diabetes , receptor , diabetes mellitus , obesity
Aim: By acting as both insulin sensitizers and lipid‐lowering agents, dual‐acting peroxisome proliferator‐activated receptors α/γ (PPARα/γ) agonists may be used to improve glucose tolerance in type 2 diabetic patients without inducing adiposity and body weight gain. Here, in an animal model of obesity and insulin resistance, the metabolic response to cevoglitazar, a dual PPARα/γ, was characterized using a combination of in vivo and ex vivo magnetic resonance methodologies and compared to treatment effects of fenofibrate, a PPARα agonist, and pioglitazone, a PPARγ agonist. Methods: Four groups of fatty Zucker rats: (i) Vehicle; (ii) fenofibrate 150 mg/kg; (iii) pioglitazone 30 mg/kg; and (iv) cevoglitazar 5 mg/kg were investigated before and after treatment. Animals were fed a fat‐enriched (54% kcal fat) diet for 6 weeks, 2 weeks high of fat–exposure alone followed by a 4‐week dosing period. Results and conclusions: Cevoglitazar was as effective as pioglitazone at improving glucose tolerance. However, unlike pioglitazone, both fenofibrate and cevoglitazar reduced BW gain and adiposity, independent of food intake. All three treatment regimens normalized intramyocellular lipids. Metabolic profiling showed that in the muscle cevoglitazar improves the lipid profile via both PPARα‐ and PPARγ‐mediated mechanisms. Pioglitazone reduced hepatic lipid accumulation, while cevoglitazar and fenofibrate reduced hepatic lipid concentration below baseline levels (p < 0.05). Metabolic profiling showed that in the liver, cevoglitazar functions largely through PPARα agonism resulting in increased β‐oxidation. Cevoglitazar only induced small changes to the lipid composition of visceral fat. In subcutaneous fat, however, cevoglitazar induced changes similar to those observed with fenofibrate suggesting export of fatty acids from this depot.