Distinct Roles of Dietary Fat and Sugar in the Development of Obesity, Insulin Resistance, Atherosclerosis and Cardiac Dysfunction in LDL Receptor Knockout Mice

The increased consumption of high caloric foods has been associated with the obesity epidemic and a higher incidence of cardiometabolic disease, but the specific role of dietary fat and sugar remains unclear. There is growing evidence that high intake of added sugar contributes to cardiovascular disease (CVD) but whether this is independent from high fat content in the diet remains to be established. To this end, our objective was to determine the impact of high sucrose intake on the features of metabolic syndrome and CVD in a mouse model of atherosclerosis. We used atherosclerosis prone LDLr −/− ApoB 100/100 (LRKOB100) mouse fed either a low‐fat/high‐sucrose (LFHS) or a high‐fat/low‐sucrose (HFLS) diet supplemented with 0.2% cholesterol for 24 weeks. Body weight gain and whole‐body fat mass were greater in HFLS‐fed vs LFHS‐fed mice. HFLS feeding promoted higher liver triglyceride (TG) deposition and plasma hypercholesterolemia when compared to LFHS feeding. HFLS‐fed animals were more insulin resistant than LFHS as revealed by a higher HOMA‐IR index. Unexpectedly, while LFHS‐fed mice were less prone to metabolic impairments, they had significant atherosclerosis development as revealed by extensive aortic plaque formation in comparison to HFLS‐fed mice. Consistent with atherosclerotic plaque formation, echocardiography further suggested that LFHS‐fed LRKOB100 mice developed left ventricle eccentric hypertrophy (LVEH) after only 12 weeks of feeding as compared to HFLS‐fed mice. Determination of the inflammatory status by multiplex analysis revealed that HFLS‐fed mice had elevated hepatic IFN‐γ, circulating MCP‐1 and PAI‐1. Conversely, LFHS‐related atherosclerosis was linked with increased hepatic levels of IL‐1β, IL‐6, RANTES and TNF‐α. In addition to hepatic inflammation, LFHS fed animals showed higher amount of TNF‐α and IFN‐γ in visceral adipose tissue, consistent with activation of metabolic inflammation. Our results indicate that dietary sugar and fat have distinct roles in the development of cardiometabolic diseases in LRKOB100 mice. While high fat intake promotes obesity and metabolic alterations, high sugar intake promotes atherosclerosis and cardiac dysfunction, with a major effect on the hepatic inflammatory profile. Further investigations are needed to unravel the underlying mechanisms by which high sugar intake promotes the atherosclerotic process. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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