Exercise Does Not Protect against Peripheral and Central Effects of a High Cholesterol Diet Given Ad libitum in Old ApoE−/− Mice

Abstract

Aim: Advanced atherosclerosis increases inflammation and stroke risk in the cerebral vasculature. Exercise is known to improve cardio-metabolic profiles when associated with a caloric restriction, but it remains debated whether it is still beneficial without the dietary control. The aim of this study was to determine both the peripheral and central effects of exercise training combined with a cholesterol-rich diet given ad libitum in old ApoE−/− mice.Methods: Forty-five-weeks old obese ApoE−/− mice fed with a high cholesterol diet ad libitum were divided into Exercise-trained (EX; running wheel free access) and Sedentary (SED) groups. Insulin tolerance and brain imaging were performed before and after the twelve-weeks training. Tissue insulin resistance, oxidative stress, and inflammation markers in plasma, aorta, and brain were then assessed.Results: In EX ApoE−/− mice, no beneficial effect of exercise was observed on weight, abdominal fat, metabolic parameters, oxidative stress, or inflammation compared to SED. Despite the regular exercise training in ApoE−/− EX mice (mean of 12.5 km/week during 12 weeks), brain inflammation imaging score was significantly associated with increased blood brain barrier (BBB) leakage evaluated by imaging follow-up (r2 = 0.87; p = 0.049) with a faster evolution compared to SED ApoE−/−mice.Conclusion: We conclude that in a context of high cardio-metabolic risk, exercise does not provide any protective effect in old ApoE−/− animals under high cholesterol diet given ad libitum. Peripheral (insulin sensitivity and oxidative/inflammatory status) but also central features (BBB preservation and protection against inflammation) did not show any benefits of exercise. Indeed, there was a fast induction of irreversible brain damage that was more pronounced in exercise-trained ApoE−/− mice.

The Effects of Endurance Exercise and Diet on Atherosclerosis in Young and Aged ApoE^–/– and Wild-Type Mice

“…Fat accumulation in the periphery and reduced release of leptin from adipose tissue over time lead to a negative influence on learning and memory in these mice [50]. It has been reported that aged ApoE -/-mice on a high-fat diet have a less robust blood-brain barrier accompanied by more neuroinflammation, and that this effect is not rescued by exercise [29]. Moreover, the type of food intake can greatly impact the metabolic and inflammatory state.…”

Alzheimer’s disease: A matter of blood–brain barrier dysfunction?

“…Apoe −/− mice lacking mouse apolipoprotein E (Apoe) develop BBB breakdown, as shown by accumulation of perivascular IgG, fibrinogen, thrombin, and hemosiderin deposits; leakage of Evans blue, different exogenous tracers, or MRI contrast agents; penetration of N -methyl- d -aspartate receptor antibodies; loss of tight junctions; basement membrane degeneration; and loss of perivascular pericytes ( Fullerton et al, 2001 ; Methia et al, 2001 ; Mulder et al, 2001 ; Hafezi-Moghadam et al, 2007 ; Nishitsuji et al, 2011 ; Bell et al, 2012 ; Hammer et al, 2014 ; Soto et al, 2015 ; Castillo-Gomez et al, 2016 ; Di Cataldo et al, 2016 ; Table 2 ). These studies indicate that Apoe is essential for maintaining BBB integrity.…”

Central and peripheral effects of physical exercise without weight reduction in obese and lean mice

“…In old ApoE −/− mice fed a high-cholesterol diet exercise had marked effects on brain, including decreased inflammation and oxidative stress, as shown by MRI. However, these effects were seen only if dietary intake was controlled whereas ad libitum feeding, as used in our study, abrogated the benefits of exercise [ 68 , 69 ], which could be related to such a discrete effect of exercise on hypothalamic gene expression we observed.…”