Published Online
on November 8, 2004

A more recent version of this article appeared on November 16, 2004

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Submitted on June 24, 2004
Revised on July 28, 2004
Accepted on August 3, 2004

Weight Loss-Associated Induction of Peroxisome Proliferator-Activated Receptor- and Peroxisome Proliferator-Activated Receptor- Correlate With Reduced Atherosclerosis and Improved Cardiovascular Function in Obese Insulin-Resistant Mice

Wim Verreth MECGB, Dieuwke De Keyzer MECGB, Michel Pelat PhD, Peter Verhamme MD, PhD, Javier Ganame , John K. Bielicki PhD, Ann Mertens PhD, MD, Rozenn Quarck PhD, Nora Benhabilès PhD, Gérard Marguerie PhD, Bharti Mackness PhD, Mike Mackness PhD, Ewa Ninio PhD, Marie-Christine Herregods PhD, MD, Jean-Luc Balligand PhD, MD, and Paul Holvoet PhD^*

From the Cardiovascular Research Unit of the Center for Experimental Surgery and Anesthesiology (W.V., D.D.K., P.V., A.M., R.Q., P.H.), Department of Cardiology (J.G., M.-C.H.), Katholieke Universiteit Leuven, and the Department of Medicine, Unit of Pharmacology and Therapeutics, Université Catholique de Louvain (M.P., J.-L.B.), Belgium; Lawrence Berkeley National Laboratory, Berkeley, Calif (J.K.B.); the University of Manchester, Department of Medicine, Manchester Royal Infirmary, Manchester, UK (B.M., M.M.); and Clinigenetics, Nimes (N.B., G.M.), and INSERM U525, Institut Fédératif CMV, Université Pierre et Marie Curie, Paris (E.N.), France.

^* To whom correspondence should be addressed. E-mail: paul.holvoet{at}med.kuleuven.ac.be.

Background--Weight loss in obese insulin-resistant but not in insulin-sensitive persons reduces coronary heart disease risk. To what extent changes in gene expression are related to atherosclerosis and cardiovascular function is unknown.

Methods and Results--We studied the effect of diet restriction-induced weight loss on gene expression in the adipose tissue, the heart, and the aortic arch and on atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia, and insulin resistance are associated with hypertension, impaired left ventricular function, and accelerated atherosclerosis in those mice. Compared with lean mice, peroxisome proliferator-activated receptors (PPAR)- and PPAR- expression was downregulated in obese double-knockout mice. Diet restriction caused a 45% weight loss, an upregulation of PPAR- and PPAR-, and a change in the expression of genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress, and inflammation, most of which are under the transcriptional control of these PPARs. Changes in gene expression were associated with increased insulin sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. PPAR- and PPAR- expression was inversely related to plaque volume and to oxidized LDL content in the plaques.

Conclusions--Induction of PPAR- and PPAR- in adipose tissue, heart, and aortic arch is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight loss. Improved lipid metabolism and insulin signaling is associated with decreased tissue deposition of oxidized LDL that increases cardiovascular risk in persons with the metabolic syndrome.

Key words: atherosclerosis • circadian rhythm • genes • lipoproteins • obesity

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