Fasting Mimicking Diet cycles prevent effects of a high fat diet on cardiometabolic risk factors and lifespan

Diet-induced obesity is the central cause of diabetes, cardiovascular disease as well as metabolic syndrome. Here, we have studied the efficacy of cycles of a 4-5 day fasting mimicking diet (FMD) in inhibiting high-fat, high calorie diet (HFCD) -induced obesity in mature female C57BL/6 mice. We show that a monthly 5-day cycle of FMD inhibit HFCD-mediated obesity by causing a reduction in calorie intake and accumulation of visceral and subcutaneous fat depots without lean body mass loss. FMD cycles also increase cardiac vascularity, function and stress resistance, and reverse the hypercholesterolemia caused by the HFCD. The sustained activation of adipocyte genes associated with mitochondrial metabolism and biogenesis and the sustained ketogenesis in the HFCD-fed mice subjected to monthly cycles of FMD indicate a reprogramming of fat cell metabolism that is likely to be at the center of obesity reversal. All these improvements could explain the protection from early mortality elicited by the high-fat, high calorie diet. Overall design: 18 C57BL/6 mice were divided into 3 groups and were fed ad libitum either a commercial high fat and high calorie diet (HFCD) (60% calories from fat) or a control diet (10% calories from fat), or a HFCD diet combined once every 4 weeks with cycles of a 5 day FMD (HFCD+FMD). Starting at cycle 6, the 5 day FMD was followed by 2 days of a control diet before the switch to HFCD. Heart and adipose tissue were harvested after 11 cycles of FMD, 4 days after the end of FMD cycle. RNA samples were extracted using the RNeasy Mini Kit following instructions (Qiagen). Libraries were built using the KAPA RNA Hyper+RiboErase HMR kit (Roche) and sequenced on an Illumina HiSeq3000 machine.