Weight Loss–Associated Induction of Peroxisome Proliferator–Activated Receptor-α and Peroxisome Proliferator–Activated Receptor-γ Correlate With Reduced Atherosclerosis and Improved Cardiovascular Function in Obese Insulin-Resistant Mice
Open accessAbstract
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)-α and PPAR-γ expression was downregulated in obese double-knockout mice. Diet restriction caused a 45% weight loss, an upregulation of PPAR-α and PPAR-γ, 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-α and PPAR-γ expression was inversely related to plaque volume and to oxidized LDL content in the plaques. Conclusions— Induction of PPAR-α and PPAR-γ 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.
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In animal models of obesity, most in vivo studies reveal mildly impaired systolic function that is absent in younger animals (<12 wk of age) but becomes evident between 12 and 20 wk of age.
“Generally, most studies reveal evidence of mildly impaired systolic function in vivo that is absent in younger animals (<12 wk of age) but become evident between 12 and 20 wk of age (34, 53, 313, 357, 361, 388).”
From Cardiac remodeling in obesity (2008) · cites this paper as [361]
Caloric restriction in ob/ob mice on the LDLR null background leads to a 45% reduction in body weight, reduced atherosclerosis, improved glucose homeostasis, reduced markers of inflammation, and normalization of cardiac function.
“Caloric restriction leads to a 45% reduction in body weight, reduced atherosclerosis, improved glucose homeostasis, reduced markers of inflammation, and normalization of cardiac function (361).”
From Cardiac remodeling in obesity (2008) · cites this paper as [361]
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References 57 · Cited by 131
Research works printed but not linked: 1
- Klemm DJ, Leitner JW, Watson P, et al. Insulin-induced adipocyte differ- entiation: activation of CREB rescues adipogenesis from the arrest caused by inhibition of prenylation. J Biol Chem. 2001;276:28430 -28435.
- Authors
- Verreth, W., De Keyzer, D., Pelat, M., Verhamme, P., Ganame, J., Bielicki, J. K., Mertens, A., Quarck, R., Benhabilès, N., Marguerie, G., Mackness, B., Mackness, M., Ninio, E., Herregods, M.-C., Balligand, J.-L., & Holvoet, P.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- 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 ...
- Manchester Royal Infirmary (GB)
- ORCID
- Venue
- Circulation
- Published
- 2004-11-16
- Volume
- 110
- Issue
- 20
- Pages
- 3259-3269
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2130768675
- Cited by
- 131
- References
- 57
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 1 · 2019: 1 · 2018: 4 · 2017: 2 · 2016: 8 · 2015: 4 · 2014: 9 · 2013: 8 · 2012: 9
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- DIAL (Catholic University of Leuven) (submittedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Vlaamse regering
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- weight loss, PPARα, PPARγ, atherosclerosis, insulin resistance, obesity, leptin deficiency, LDL receptor deficiency, dietary restriction, cardiovascular function, oxidized LDL, hypertriglyceridemia, adipose tissue gene expression, heart, aortic arch, metabolic syndrome, circadian blood pressure variation, ejection fraction, plaque volume
- MeSH terms
- Adipose Tissue, Animals, Aorta, Thoracic, Arteriosclerosis, Autoantibodies, Circadian Rhythm, Echocardiography, Gene Expression Regulation, Genotype, Glucose, Heart Function Tests, Inflammation, Insulin Resistance, Lipoproteins, LDL, Mice, Inbred C57BL, Mice, Obese, Myocardium, Obesity, Receptors, LDL, Transcription, Genetic, Hypertriglyceridemia, Weight Loss, Up-Regulation, Mice, Knockout, Oxidative Stress, Leptin, PPAR alpha, PPAR gamma, Mice
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