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J. Lipid Res.
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A more recent version of this article appeared on November 1, 2002

Papers In Press, published online ahead of print August 16, 2002
J. Lipid Res., doi:10.1194/jlr.M200127-JLR200
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Submitted on March 18, 2002
Revised on May 27, 2002
Accepted on August 6, 2002

AZ 242, a Novel PPARalpha /gamma Agonist with Beneficial Effects on Insulin Resistance, Carbohydrate and Lipid Metabolism in ob/ob Mice and Obese Zucker Rats

Bengt Ljung, Krister Bamberg, Björn Dahllöf, Ann Kjellstedt, Nicholas D. Oakes, Jörgen Östling, Lennart Svensson, and Germán Camejo

Integrative PHARMACOLOGY, Research Area CV&GI, Mölndal S 431 83

Corresponding Author: Bengt.Ljung{at}astrazeneca.com

ABSTRACT Abnormalities in FA metabolism underlie the development of insulin resistance and alterations in glucose metabolism, features characteristic of the metabolic syndrome and type 2 diabetes that can result in an increased risk of cardiovascular disease. We present pharmacodynamic effects of AZ 242, a novel PPARalpha /gamma agonist. AZ 242 dose-dependently reduced the hypertriglyceridemia, hyperinsulinemia and hyperglycemia of ob/ob diabetic mice. Euglycemic hyperinsulinemic clamp studies showed that treatment with AZ 242 (1 mu mol/kg/d) restored insulin sensitivity of obese Zucker rats and decreased insulin secretion. In vitro, reporter gene assays, AZ 242 activated human PPARalpha and PPARgamma with EC50 in the mu molar range. It also induced differentiation in 3T3-L1 cells, an established PPARgamma effect, and caused up-regulation of L-FABP in HepG-2 cells, a PPARalpha mediated effect in vitro. PPARalpha -mediated effects of AZ 242 in vivo were documented by induction of hepatic cytochrome P 450-4A in mice. The results indicate that the dual PPARalpha /gamma agonism of AZ 242 reduces insulin resistance and has beneficial effects on FA and glucose metabolism. This effect profile could provide a suitable therapeutic approach to the treatment of type 2 diabetes, metabolic syndrome and associated vascular risk factors


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