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.
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.
Verreth
Wim
W
Cardiovascular Research Unit of the Center for Experimental Surgery and Anesthesiology, Katholieke Universiteit Leuven, Belgium.
De Keyzer
Dieuwke
D
Pelat
Michel
M
Verhamme
Peter
P
Ganame
Javier
J
Bielicki
John K
JK
Mertens
Ann
A
Quarck
Rozenn
R
Benhabilès
Nora
N
Marguerie
Gérard
G
Mackness
Bharti
B
Mackness
Mike
M
Ninio
Ewa
E
Herregods
Marie-Christine
MC
Balligand
Jean-Luc
JL
Holvoet
Paul
P
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
D001323:Autoantibodies; D020738:Leptin; D008077:Lipoproteins, LDL; D047493:PPAR alpha; D047495:PPAR gamma; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D005947:Glucose