Title: Weight-loss-associated induction of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-gamma correlate with reduced atherosclerosis and improved cardiovascular function in obese insulin-resistant mice
Authors: Verreth, Wim ×
De Keyzer, Dieuwke
Pelat, Michel
Verhamme, Peter
Ganame, Javier
Bielicki, John K
Mertens, Ann
Quarck, Rozenn
Benhabilès, Nora
Marguerie, Gérard
Mackness, Bharti
Mackness, Mike
Ninio, Ewa
Herregods, Marie-Christine
Balligand, Jean-Luc
Holvoet, Paul #
Issue Date: Nov-2004
Publisher: American Heart Association
Series Title: Circulation vol:110 issue:20 pages:3259-69
Abstract: 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)-alpha and PPAR-gamma expression was downregulated in obese double-knockout mice. Diet restriction caused a 45% weight loss, an upregulation of PPAR-alpha and PPAR-gamma, 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-alpha and PPAR-gamma expression was inversely related to plaque volume and to oxidized LDL content in the plaques. CONCLUSIONS: Induction of PPAR-alpha and PPAR-gamma 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.
ISSN: 0009-7322
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Atherosclerosis and Metabolism (-)
Cardiovascular Developmental Biology
Molecular and Vascular Biology
× corresponding author
# (joint) last author

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