Caloric restriction (CR) is a non-pharmacological intervention in obese patients which provides huge health benefits against metabolic and cardiovascular diseases. However, the major hurdle in CR as an intervention is the non-compliance. Here, we studied if high-fat diet plays a causal role in mitigating the metabolic effects of CR.


Six-week old C57BL/6 mice were individually housed and randomly divided into four groups and fed for 6-weeks with chow diet ad libitum or Caloric restricted (40% less calories than RD) or 40% CR on weekdays and 60% high-fat diet on weekends or 60% high-fat diet ad libitum. Metabolic test, indirect calorimetry and adipose tissue remodeling were assessed.


High-fat feeding resulted in regaining of body weight that was lost by CR. High-fat abrogated the CR-induced improvement in glucose tolerance and insulin sensitivity. Indirect calorimetry showed a robust improvement in substrate utilization by CR, independent of activity. Interestingly, high-fat acutely disrupted CR-mediated improvement in substrate flexibility. When we assessed the gonadal (gWAT) and inguinal white adipose tissue (iWAT), CR induced adipose tissue remodeling that include a decrease in adipocyte size, appearance of multilocular adipocyte and an increase in UCP-1 expression, suggesting browning of WAT. High-fat feeding attenuated CR induced browining of adipose tissue. High-fat-mediated dysregulation of adipose tissue remodeling is associated with a decrease in the activation of AMPK signaling in the adipose tissue.


Our study reiterates that High-fat feeding mitigates the metabolic effect of CR by disrupting the metabolic flexibility and inhibiting browning of the adipose tissue. Strict following of CR produce remarkable health benefits.