Postnatal overconsumption of fat has been shown to increase the susceptibility to metabolic disease in the later life. There is emerging evidence to suggest that certain interventions in the adulthood can have prolonged metabolic effects beyond the intervention duration, namely the legacy effect (N Eng J Med. 2008;359:1618-20; PLoS One. 2012;7:e42115). However, it remains unclear that whether prior exposure to high fat (HF) diets in adulthood also has long-term metabolic effects after the cessation of the HF feeding.
This study was set to test the hypothesis that prior intermittent exposures to a HF diet exacerbate the metabolic syndrome in response to subsequent feeding of the HF diet. To test this hypothesis, we pre-exposed adult mice (12 wks) a HF diet twice with each episode for 2 wks followed by 2 wks of washout with a chow (CH) diet. The mice were then challenged by feeding the same HF diet for 6 weeks to examine the legacy effect. In contrast to our hypothesis, the results showed that prior exposures to the HF diet significantly lessened body weight gain and visceral adiposity during the period of subsequent HF feeding. Along with the reduced obesity, both glucose tolerance and insulin tolerance were improved. Interestingly, these protective legacy effects were not observed in high fructose diet under the same conditions and they occurred without a reduction in calorie intake. Further analysis revealed that these legacy effects were associated with persistent increases in plasma FGF21 and enhanced metabolic capabilities in both muscle and adipose tissue.
These findings indicate that HF diet preconditioning induces protective legacy effects against subsequent consumption of the HF diet. The mechanism involves enhanced metabolic capacity in muscle and adipose tissue. This paradoxical legacy effect may offer a unique paradigm to explore novel factors with anti-obesity properties.