Alternate day fasting aggravates atherosclerosis through the suppression of hepatic ATF3 in Apoe^(-/-)mice

Atherosclerosis is the major contributor to cardiovascular mortality worldwide.Alternate day fasting(ADF)has gained growing attention due to its metabolic benefits.However,the effects of ADF on atherosclerotic plaque formation remain inconsistent and controversial in atherosclerotic animal models.The present study was designed to investigate the effects of ADF on atherosclerosis in apolipoprotein E-deficient(Apoe^(-/-))mice.Eleven-week-old male Apoe^(-/-)mice fed with Western diet(WD)were randomly grouped into ad libitum(AL)group and ADF group,and ADF aggravated both the early and advanced atherosclerotic lesion formation,which might be due to the disturbed cholesterol profiles caused by ADF intervention.ADF significantly altered cholesterol metabolism pathways and down-regulated integrated stress response(ISR)in the liver.The hepatic expression of activating transcription factor 3(ATF3)was suppressed in mice treated with ADF and hepatocyte-specific overexpression of Aft3 attenuated the effects of ADF on atherosclerotic plaque formation in Apoe^(-/-)mice.Moreover,the expression of ATF3 could be regulated by Krüppel-like factor 6(KLF6)and both the expressions of ATF3 and KLF6 were regulated by hepatic cellular ISR pathway.In conclusion,ADF aggravates atherosclerosis progression in Apoe^(-/-)mice fed on WD.ADF inhibits the hepatic ISR signaling pathway and decreases the expression of KLF6,subsequently inhibiting ATF3 expression.The suppressed ATF3 expression in the liver mediates the deteriorated effects of ADF on atherosclerosis in Apoe^(-/-)mice.The findings suggest the potentially harmful effects when ADF intervention is applied to the population at high risk of atherosclerosis.

Assessing the evidence for weight loss strategies in people with and without type 2 diabetes

This review will examine topical issues in weight loss and weight maintenance in people with and without diabetes. A high protein, low glycemic index diet would appear to be best for 12-mo weight maintenance in people without type 2 diabetes. This dietary pattern is currently beingexplored in a large prevention of diabetes intervention. Intermittent energy restriction is useful but no better than daily energy restriction but there needs to be larger and longer term trials performed. There appears to be no evidence that intermittent fasting or intermittent severe energy restriction has a metabolic benefit beyond the weight loss produced and does not spare lean mass compared with daily energy restriction. Meal replacements are useful and can produce weight loss similar to or better than food restriction alone. Very low calorie diets can produce weight loss of 11-16 kg at 12 mo with persistent weight loss of 1-2 kg at 4-6 years with a very wide variation in long term results. Long term medication or meal replacement support can produce more sustained weight loss. In type 2 diabetes very low carbohydrate diets are strongly recommended by some groups but the long term evidence is very limited and no published trial is longer than 12 mo. Although obesity is strongly genetically based the microbiome may play a small role but human evidence is currently very limited.