The obesity epidemic and dietary interventions

Diet-induced obesity is a lifestyle disease caused by abundant access to food, overfeeding and sedentary lifestyle. Obesity has been categorized as a chronic disease and an epidemic by the Centre for Disease Control and the World Health Organization (https://www.who.int/activities/controlling-the-global-obesity-epidemic, https://www.cdc.gov/obesity/about-obesity/index.html). Dietary interventions involving calorie restriction or periods of fasting have been shown to be very effective in improving the health in obesity, cardiovascular disease (CVD) and various other diseases (Longo et al., 2021). However, most of the dietary interventions require radical lifestyle changes and are thus difficult to adhere to in the long term, limiting their utility and acceptability for mass adoption. Chronic interventions also have the risk of causing malnutrition as well loss of lean body mass which can have detrimental effects on health in the long term (Cava et al., 2017).

To overcome the limitations posed by the chronic interventions our lab developed a periodic plant-based low caloric fasting-mimicking diet (FMD) containing high dietary fat but low protein and sugar, which is adopted for only 4-5 days periodically but has  benefits comparable to those of chronic dietary restrictions but without malnutrition or loss of lean mass (Brandhorst et al., 2015). Our previous studies reported that FMD cycles lasting 4-5 days with frequencies ranging from once every 10 days to once a month have a range of health benefits in mice, including increased lifespan, decrease and delay in cancer incidence, reduced autoimmunity and multiple sclerosis symptoms, reversal of type 1 and type 2 diabetes pathology, modulation of gut microbiota and intestinal regeneration, and reversal of inflammatory bowel disease pathology (Longo et al., 2021; Wei et al., 2017).

FMD, obesity, and lifespan

https://www.nature.com/articles/s42255-021-00469-6

In our current paper, we show that in a mice model of diet-induced obesity, a High-fat and calorie diet (HFCD) causes increased adiposity and body weight and reduces lifespan (Mishra et al., 2021). We found that periodic cycles of 5-day FMD followed by 2-day of control diet once every 4 weeks not only prevents obesity but also restores the normal lifespan in mice that are otherwise fed an HFCD. The prevention of obesity and restoration of normal lifespan in mice eating HFCD but undergoing monthly cycles of FMD is also accompanied by the return in serum and metabolic markers of cardiovascular disease and metabolic syndrome to levels comparable to those in mice fed on a control diet. This includes lower blood glucose and serum cholesterol as well as improved glucose and insulin tolerance (a marker of insulin resistance).

Cycles of FMD also lead to improvement in multiple parameters of CVD. The HFCD + FMD mice perform better than HFCD mice when treated with the cardiotoxin dobutamine. HFCD + FMD mice were also better in terms of markers of cardiac ageing and showed increased heart capillary density compared to HFCD mice. Mice on HFCD + FMD also had lower left ventricle internal diameter (LVID) which increases with HFCD.

Interestingly, we found that cycles of FMD prevented the increase in leptin caused by a HFCD. Leptin is a hormone that regulates appetite and food intake and is thus obesity. Overall, this led to significantly reduced calorie intake in mice on HFCD plus FMD cycles when compared to mice on a continuous HFCD.

Transcriptome sequencing of visceral adipose tissue revealed increased mitochondrial metabolism and biogenesis in mice treated with FMD cycles. Previous studies on continuous calorie restriction had identified similar pathways to be activated during calorie restriction (Kim et al., 2016). Our study shows that in the case of FMD, these pathways remain activated days after the end of the fasting cycle, suggesting a long-term metabolic reprogramming induced by the cycles of FMD. In fact, mice undergoing FMD cycles also had higher serum ketone body levels even 4 days after the end of the FMD cycle. Ketone bodies play an important role in mediating fasting induced benefits but also serve as an indicator of sustained fat catabolism, which may explain the fat loss.

 In summary, we show that FMD applied for only 5 days a month can counterbalance most of the negative effects of a high fat diet consumed for the rest of the month. Most importantly, it restores the reduced lifespan caused by HFCD possibly by inducing a long-term metabolic reprogramming whereby the animals remain in the ketogenic state days after the end of the FMD cycle. These results, together with recently published clinical trials indicate that periodic fasting mimicking diets could represent an alternative to continuous dietary restrictions or pharmacological therapies.

Also see the news and views article by Heilbronn, 2021 for more.

https://www.nature.com/articles/s42255-021-00472-x 

References:

1. Longo, V. D., Di Tano, M., Mattson, M. P. & Guidi, N. Intermittent and periodic fasting, longevity and disease. Nat. Aging 1, 47–59 (2021).
2. Cava, E., Yeat, N. C. & Mittendorfer, B. Preserving healthy muscle during weight loss. Adv. Nutr. 8, 511–519 (2017).
3. Brandhorst, S. et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 22, 86–99 (2015).
4. Wei, M. et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci. Transl. Med. 9, eaai8700 (2017).
5. Kim, S. S. et al. Whole‑transcriptome analysis of mouse adipose tissue in response to short‑term caloric restriction. Mol. Genet. Genomics 291, 831–847 (2016).
6. Mishra, A. et al. Fasting-mimicking diet prevents high-fat diet effect on cardiometabolic risk and lifespan. Nat. Metab. (2021) doi:10.1038/s42255-021-00469-6.

7. Heilbronn, L. K. Periodic fasting prevents fat penalties in females. Nat. Metab. (2021) doi:10.1038/s42255-021-00472-x.