Laís R Perazza1, Patricia L Mitchell1, Benjamin A H Jensen2, Noëmie Daniel1, Marjorie Boyer3, Thibault V Varin1, Rihab Bouchareb3, Renato T Nachbar3, Michaël Bouchard4, Mylène Blais4, Andréanne Gagné3, Philippe Joubert3, Gary Sweeney5, Denis Roy6, Benoit J Arsenault3, Patrick Mathieu3, André Marette7. 1. Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada; Institute of Nutraceuticals and Functional Foods, Laval University, Quebec City, Quebec, Canada. 2. Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Human Genomics and Metagenomics in Metabolism, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 3. Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada. 4. Sherbrooke Research and Development Centre, Agriculture and Agri-Food, Canada, Sherbrooke, Québec, Canada. 5. Department of Biology, York University, Toronto, Ontario, Canada. 6. Institute of Nutraceuticals and Functional Foods, Laval University, Quebec City, Quebec, Canada. 7. Quebec Heart and Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada; Institute of Nutraceuticals and Functional Foods, Laval University, Quebec City, Quebec, Canada. Electronic address: andre.marette@criucpq.ulaval.ca.
Abstract
BACKGROUND AND AIMS: Poor dietary habits contribute to the obesity pandemic and related cardiovascular diseases but the respective impact of high saturated fat versus added sugar consumption remains debated. Herein, we aimed to disentangle the individual role of dietary fat versus sugar in cardiometabolic disease progression. METHODS: We fed pro-atherogenic LDLr-/-ApoB100/100 mice either a low-fat/high-sucrose (LFHS) or a high-fat/low-sucrose (HFLS) diet for 24 weeks. Weekly body weight gain was registered. 16S rRNA gene-based gut microbial analysis was performed to investigate gut microbial modulations. Intraperitoneal insulin (ipITT) and oral glucose tolerance test (oGTT) were conducted to assess glucose homeostasis and insulin sensitivity. Cytokines were assessed in fasted plasma, epididymal white adipose tissue and liver lysates. Heart function was evaluated by echocardiography. Aortic atheroma lesions were quantified according to the en face technique. RESULTS: HFLS feeding increased obesity, insulin resistance and dyslipidemia compared to LFHS feeding. Conversely, high sucrose consumption decreased gut microbial diversity while augmenting inflammation and the adaptative immune defense against metabolic endotoxemia and reduced macrophage cholesterol efflux capacity. This led to more severe cardiovascular complications as revealed by remarkably high level of atherosclerotic lesions and the early development of cardiac dysfunction in LFHS vs HFLS fed mice. CONCLUSIONS: We uncoupled obesity-associated insulin resistance from cardiovascular diseases and provided novel evidence that dietary sucrose, not fat, is the main driver of metabolic inflammation accelerating severe atherosclerosis in hyperlipidemic mice.
BACKGROUND AND AIMS: Poor dietary habits contribute to the obesity pandemic and related cardiovascular diseases but the respective impact of high saturated fat versus added sugar consumption remains debated. Herein, we aimed to disentangle the individual role of dietary fat versus sugar in cardiometabolic disease progression. METHODS: We fed pro-atherogenic LDLr-/-ApoB100/100 mice either a low-fat/high-sucrose (LFHS) or a high-fat/low-sucrose (HFLS) diet for 24 weeks. Weekly body weight gain was registered. 16S rRNA gene-based gut microbial analysis was performed to investigate gut microbial modulations. Intraperitoneal insulin (ipITT) and oral glucose tolerance test (oGTT) were conducted to assess glucose homeostasis and insulin sensitivity. Cytokines were assessed in fasted plasma, epididymal white adipose tissue and liver lysates. Heart function was evaluated by echocardiography. Aortic atheroma lesions were quantified according to the en face technique. RESULTS: HFLS feeding increased obesity, insulin resistance and dyslipidemia compared to LFHS feeding. Conversely, high sucrose consumption decreased gut microbial diversity while augmenting inflammation and the adaptative immune defense against metabolic endotoxemia and reduced macrophage cholesterol efflux capacity. This led to more severe cardiovascular complications as revealed by remarkably high level of atherosclerotic lesions and the early development of cardiac dysfunction in LFHS vs HFLS fed mice. CONCLUSIONS: We uncoupled obesity-associated insulin resistance from cardiovascular diseases and provided novel evidence that dietary sucrose, not fat, is the main driver of metabolic inflammation accelerating severe atherosclerosis in hyperlipidemic mice.
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