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.
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.
  
  
  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.
authors.affiliation: Cardiovascular Research Unit of the Center for Experimental Surgery and Anesthesiology, Katholieke Universiteit Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Verreth
authors.forename: Dieuwke
authors.initials: D
authors.lastname: De Keyzer
authors.forename: Michel
authors.initials: M
authors.lastname: Pelat
authors.forename: Peter
authors.initials: P
authors.lastname: Verhamme
authors.forename: Javier
authors.initials: J
authors.lastname: Ganame
authors.forename: John K
authors.initials: JK
authors.lastname: Bielicki
authors.forename: Ann
authors.initials: A
authors.lastname: Mertens
authors.forename: Rozenn
authors.initials: R
authors.lastname: Quarck
authors.forename: Nora
authors.initials: N
authors.lastname: Benhabilès
authors.forename: Gérard
authors.initials: G
authors.lastname: Marguerie
authors.forename: Bharti
authors.initials: B
authors.lastname: Mackness
authors.forename: Mike
authors.initials: M
authors.lastname: Mackness
authors.forename: Ewa
authors.initials: E
authors.lastname: Ninio
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Herregods
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Balligand
authors.forename: Paul
authors.initials: P
authors.lastname: Holvoet
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D001323:Autoantibodies / Q000032:analysis; D002940:Circadian Rhythm; D004452:Echocardiography; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006334:Heart Function Tests; D015228:Hypertriglyceridemia / Q000209:etiology / Q000517:prevention & control; D007249:Inflammation; D007333:Insulin Resistance; D020738:Leptin / Q000172:deficiency / Q000235:genetics; D008077:Lipoproteins, LDL / Q000032:analysis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000178:diet therapy* / Q000235:genetics / Q000473:pathology; D018384:Oxidative Stress; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics; D047495:PPAR gamma / Q000096:biosynthesis* / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation; D015431:Weight Loss
chemical_list: D001323:Autoantibodies; D020738:Leptin; D008077:Lipoproteins, LDL; D047493:PPAR alpha; D047495:PPAR gamma; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D005947:Glucose