Intermittent Fasting and Muscle Lipid Metabolism: Commentary on: Liu et al “Effects of intermittent fasting or calorie restriction on markers of lipid metabolism in human skeletal muscle”

intermittent fasting, alternate day fasting, muscle lipid metabolism, nonesterified fatty acids, obesity

Intermittent fasting (IF) has emerged as an alternative to daily calorie restriction (CR) to improve metabolic health. Alternate-day fasting (ADF) is the most studied form of intermittent fasting to date. ADF consists of a “feast day” alternated with a “fast day.” The feast day involves ad libitum eating with no restrictions on food quality and quantity for 24 hours. The “fast day” limits intake to 0 kcal/d (termed zero-calorie ADF) or 25% of energy needs (termed modified ADF) for the following 24 hours.

More than a dozen trials have examined the efficacy of ADF in humans (1, 2). Results from these trials suggest ADF is as effective as daily CR for weight loss and metabolic disease risk reduction (1, 2). Specifically, ADF appears to produce moderate weight loss (3%-8%) and may decrease metabolic disease risk by lowering low-density lipoprotein cholesterol levels, triglycerides, blood pressure, and insulin resistance (1, 2). More recently, it has been proposed that owing to the daily metabolic switch that occurs between the anabolic fed state and catabolic fasted state during IF, these regimens may stimulate lipid turnover more than daily restriction (3).

In a new study, Liu et al (4) examined the effect of IF vs CR on lipid metabolism in human skeletal muscle. The study is a secondary analysis of an 8-week randomized control trial in women with overweight or obesity (5). In the original study (5), 88 female participants were randomly assigned into 1 of 4 groups: (1) CR70, where participants ate 70% of energy needs daily; (2) IF70, where participants performed ADF 3 days a week with a 30% total weekly energy deficit; (3) IF100, where participants performed ADF with no energy deficit; or (4) a control group. However, the control group was not included in this secondary analysis. On the fast day, the IF70 group and the IF100 group ate a breakfast before 8 am (~35% of energy needs) and then fasted for 24 hours. On the feast day, participants ate either 100% of energy needs (IF70) or 145% (IF100) of energy needs.

After 8 weeks of the intervention, the IF70 group lost more weight and fat mass than the CR70 or IF100 groups. Both fasting groups reduced the messenger RNA (mRNA) levels of the antioxidant enzymes glutathione peroxidate-1 (GPX1), superoxide dismutase-1 (SOD1), and superoxide dismutase-2 (SOD2) in skeletal muscle when compared to CR70. This key finding suggests IF may be associated with a reduction in reactive oxygen species (ROS) production. More specifically, it would appear as though lower levels of antioxidant enzymes were necessary to maintain systemic redox homeostasis, which was assessed by serum protein carbonyls. Mitochondria are a major site for ROS production. If left unchecked, these ROS can cause substantial damage to this organelle and the rest of the cell. GPX and SOD are a first-line antioxidant defense system that converts superoxide anions into less hazardous molecules (6). Taken together, these findings are paramount in that they suggest IF may reduce ROS production more so than daily restriction regimens. It will be of great interest to see whether these findings can be replicated in other population groups and with other forms of IF.

This study also found that fasting transiently increased circulating nonesterified fatty acids and perilipin 5 (PLIN5) mRNA levels in muscle. This would suggest that lipid droplet formation and storage within the myocyte was transiently augmented in response to fasting. PLIN5 has been shown to protect against lipotoxicity and stimulate lipid oxidation (7). However, in the present study (4), the increase in PLIN5 was insufficient to prevent the increase in insulin resistance induced by fasting. These findings differ from what has been previously reported in male participants after an acute fast (8). Following 60 hours of fasting, the size and number of lipid droplets in muscle increased in lean, normoglycemic men (8). The fraction of PLIN5 protein associated with the lipid droplets also increased (8). Moreover, men with the greatest increase in PLIN5-associated lipid droplets were shown to have the smallest reduction in insulin sensitivity (8). The reason the increase in PLIN5 in the present study did not influence the degree of insulin resistance during IF is unclear. The clinical implications of these transient increases in insulin resistance in response to fasting undoubtedly warrants further investigation.

The Liu et al (4) study has several strengths. This is the first study to compare the effects of IF vs CR on lipid and mitochondrial metabolism in human skeletal muscle. The trial is also advantageous in that it included 3 diet prescriptions, that is, daily CR vs an energy-matched IF group as well as an isocaloric IF group. This allowed the investigators to examine if changes in lipid metabolism were due to the energy deficit, often prescribed in ADF studies, or if the fasting itself produced these outcomes. In addition, the study used gold-standard measures to examine insulin sensitivity and lipid deposition. Specifically, the investigators used the hyperinsulinemic-euglycemic clamp and muscle biopsy to measure insulin sensitivity and lipid droplet deposition intramuscularly.

Although this study has several strengths, it also has some methodological limitations. First, the sample size was small and the study may have been underpowered to see significant changes in these secondary outcome measures. Second, the removal of the control group is also a distinct limitation. Third, it is possible that eating the large caloric load (145% of needs) in the IF100 group could have had a negative effect on the outcomes measured, dampening the positive effects of fasting. Last, the study was conducted solely in women with overweight or obesity, thus the findings may not be generalizable to men or those who are normal weight.

In summary, these findings by Lui and colleagues (4) suggest fasting may be superior to daily restriction for decreasing ROS production in women with overweight or obesity. It was also noted that fasting increased mRNA levels of PL1N5, suggesting enhanced lipid droplet formation. However, this was not sufficient to prevent the transient increase in insulin resistance induced by fasting.

Abbreviations

Abbreviations
 
• ADF

  alternate-day fasting

 
• CR

  calorie restriction

 
• IF

  intermittent fasting

 
• mRNA

  messenger RNA

 
• PLIN5

  perilipin 5

 
• ROS

  reactive oxygen species

Additional Information

Disclosure Summary: K.A.V. has received author fees from the Hachette Book Group for the book, The Every Other Day Diet. K.G. has nothing to disclose.

Data Availability

Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study.