Studies in mice by a Canadian research team have shown how intermittent fasting (IF) without any calorie restriction results in animals shedding fat and losing body weight, leads to improved glucose homeostasis, and also protects against metabolic dysfunction. The Canadian research team, led by Kyoung-Han Kim, Ph.D., at the Hospital for Sick Children in Toronto, put mice on a regime of two days of unrestricted feeding followed by one day of fasting. They found that after 16 weeks the IF animals weighed less than the control group of mice that had eaten the same volume of food, which correlated with the loss of white adipose tissue (WAT) and increased thermogenesis. The beneficial effects of IF on glucose homeostasis and liver metabolism in previously obese animals were seen after just six weeks.

Further analysis and genetic evaluation showed that the metabolic and weight loss effects seen in IF animals were mediated by IF-induced increases in vascular endothelial growth factor (VEGF) levels in WAT, which triggered alternative activation of adipose macrophage (M2) and thermogenesis. Reporting on the study, Kim concludes, “Intermittent fasting without a reduction in calorie intake can be a preventative and therapeutic approach against obesity and metabolic disorders.” The researchers describe their studies in Cell Research, in a paper entitled  “Intermittent Fasting Promotes Adipose Thermogenesis and Metabolic Homeostasis via VEGF-Mediated Alternative Activation of Macrophage.”

There is accumulating evidence to suggest that weight loss diets that involve periods of fasting, or strict calorie restriction, offer a number of biological benefits both in animal models and in humans, the researchers write. “For example, the 5:2 diet, which involves CR [caloric restriction] for 2 non-consecutive days a week and unconstrained eating the other 5 days, has become a popular IF regimen and has a potential to be considered for medical interventions.”

In fact, IF has been practiced in human clinical settings with various fasting regimens, and most studies have found beneficial health effects such as body weight reduction and increased insulin sensitivity, the authors continue. But while calorie restriction and IF are known to impact on multiple metabolic organs and tissues, to date it hasn’t been clear which tissue drives these IF-induced metabolic benefits.

The Toronto researchers first demonstrated that IF mice fed a high-fat diet consistently exhibited reduced fat mass, without changes in lean body mass, compared with control animals. The IF feeding regimen also led to improved glucose homeostasis and increased insulin sensitivity, and prevented high-fat diet–induced hepatic steatosis.

Encouragingly, when obese mice that had been fed a high-fat diet were put on the IF regimen, they demonstrated beneficial effects within just 6 weeks, including slight reduction in body weight—without changing total calorie intake—decreased WAT mass, and improved liver function and glucose homeostasis. Genetic analysis of high-fat diet control and IF animals highlighted the upregulation of genes in IF mice that were associated with reduced inflammation and increased WAT thermogenesis. Further comparison of biological pathways in IF and control animals indicated that WAT thermogenesis was driven by VEGF. In fact, VEGF knockout animals failed to demonstrate any beneficial metabolic effects of IF. Interestingly, increased IF-stimulated VEGF expression was demonstrated in WAT, but not in brown adipose tissue (BAT), other metabolic tissues, or plasma, the researchers stress.

The effects of IF on VEGF expression were also reversible. VEGF expression levels increased progressively with increased duration of fasting, but were immediately reversed on refeeding. “… these findings suggest that adipose-VEGF is required for IF-induced metabolic improvement and adipose thermogenesis,” the authors write.  Additional studies subsequently confirmed that by directly upregulating adipose-VEGF levels in mice without IF mimicked the effects of IF, and resulted in reduced body weight and reduced fat mass, lower adipose tissue weight, and improved glucose homeostasis.

VEGF triggers the creation of new vasculature and is implicated in WAT browning in response to cold and exercise. Although the mechanism that underlies the relationship hasn’t been well understood, prior studies have suggested that cold- and exercise-induced WAT browning is mediated through alternative activation of adipose macrophage. The Toronto team’s  studies in the IF mice also confirmed that the fasting cycles triggered alternative activation of adipose tissue macrophage in response to VEGF elevation, and that this macrophage activation was associated with beige adipocyte development in WAT and increased thermogenesis. 

To see whether their findings in mice may also be relevant to humans, the researchers then carried out an analysis of biochemical and genetic data from human adipose tissues, which confirmed a correlation between VEGF gene expression and M2 macrophage activation. “Together with our mouse data, these results suggest that the adipose-VEGF expression level, which is elevated by IF, is not only associated with vasculature, but is also a metabolic index indicating M2 macrophage activation and beige adipocyte development in both humans and mice,” the authors conclude.  “We demonstrate in this study that fasting is a physiological means of increasing adipose Vegfa gene expression, in addition to exercise and cold exposure. Accordingly, IF confers similar metabolic impacts as physical exercise and cold exposure (e.g., browning of WAT) with markedly increased adipose vasculature.”

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