Alternate-day fasting and exercise for reducing liver fat Original paper

In this randomized controlled trial, combining alternate-day fasting (ADF) with aerobic exercise decreased liver fat more than ADF or exercise alone in people with nonalcoholic fatty liver disease.

This Study Summary was published on March 1, 2023.

Background

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive liver fat and elevated cardiometabolic risk factors. Lifestyle interventions involving dietary modifications and increased physical activity, with the goal of inducing significant weight loss, are the cornerstone of NAFLD treatment.[1] A variety of hypocaloric diets can be effective for this task, including alternate-day fasting (ADF). However, a study had yet to directly quantify changes in liver fat from ADF or examine whether combining ADF with an exercise intervention augments improvements in cardiometabolic risk factors.

The study

In this 3-month randomized controlled trial, 80 participants (81% women, mainly Hispanic or Black, ages 23–65) with NAFLD were assigned to one of four groups:

  • ADF: participants alternated days of free eating with modified fasting days in which they consumed 600 kcal (30% of energy from fat, 55% carbohydrate, 15% protein) between 5 p.m. and 8 p.m.
  • Exercise (EX): participants completed 60 minutes of moderate-intensity aerobic exercise (65%–80% of maximum predicted heart rate) five times per week, which was supervised by the study staff.
  • ADF+exercise (COMBO): participants followed the ADF and EX interventions.
  • Control: participants were instructed to maintain current eating and exercise habits (no intervention).

At baseline and the end of the study, dietary intake was assessed using a 24-hour dietary assessment tool, and physical activity was monitored over 7 days using a pedometer.

The primary outcome was liver fat, measured using a specialized magnetic resonance imaging (MRI) technique. The secondary outcomes were anthropometrics, blood lipids, markers of glycemic control (fasting glucose, fasting insulin, HbA1c, insulin resistance assessed via HOMA-IR, and insulin sensitivity assessed via QUICKI), blood pressure, liver enzymes (ALT and AST), liver fibrosis (estimated using the FIB-4 index), and hepatokines (proteins secreted from the liver that regulate metabolic processes; FGF-21, selenoprotein P, fetuin-A).

The results

Compared to control and EX, liver fat decreased in COMBO. Additionally, liver fat nonsignificantly (p=0.05) decreased in COMBO compared to ADF (−5.48% vs. −2.25%). Compared to control, serum levels of ALT decreased in COMBO.

Compared to control and EX, body weight and fat mass decreased in COMBO. However, weight and fat loss were not different between COMBO and ADF (−4.58% vs. −5.06%; −3.24 vs. −3.32 kg).

Compared to control, fasting insulin and insulin resistance decreased and insulin sensitivity increased in COMBO. Additionally, insulin sensitivity nonsignificantly increased in COMBO compared to ADF (p=0.05) and EX (p=0.07). There were no other differences between groups.

COMBO results

image

Note

The participants had a low risk of advanced fibrosis at baseline, according to the average FIB-4 score, which may help explain the lack of effect of the interventions on fibrosis.

The researchers did not adjust for multiple comparisons, despite the inclusion of numerous outcomes, which increases the risk of false-positive results. Therefore, the results for the secondary outcomes should be interpreted with caution.

The big picture

The standout finding of this study was that, despite similar reductions in body weight and fat mass in COMBO and ADF, reductions in liver fat were greater in COMBO, suggesting that just losing weight isn’t the only important factor for reducing liver fat. To maximize these reductions, it may be pivotal to combine a hypocaloric diet with exercise.

That said, this finding (i.e., a greater reduction in liver fat in COMBO compared to ADF) was technically nonsignificant, so further trials utilizing a similar design are needed. In the meantime, other research can shed light on the question of whether exercise reduces liver fat independent of changes in body weight. If this is indeed the case, it’s possible that exercise truly had an additive effect in the summarized study.

Fortunately, this subject is quite well studied. Multiple trials have reported that exercise significantly decreases liver fat independent of weight loss.[2][3][4] According to a 2018 meta-analysis, in the absence of significant weight loss, exercise interventions reduce liver fat by 2.16%, on average, in people with NAFLD.[5] However, the addition of significant weight loss still produced larger reductions in liver fat.

The evidence is pretty clear that exercise can reduce liver fat independent of weight loss, but how much exercise is needed? The summarized study utilized a relatively demanding moderate-intensity aerobic exercise protocol (300 minutes per week), which may be an unsustainable approach for many people. This may have been why, although there were no dropouts in COMBO, 25% of the participants assigned to EX dropped out.

After 3 months, the summarized study found a nearly 5.5% reduction in liver fat in the COMBO group, which is on par with reductions yielded by other lifestyle intervention with considerably less exercise volume. In an observational study that instructed participants (including 50 with NAFLD) to reduce their energy intake and perform aerobic exercise that only moderately increased heart rate for at least 180 minutes per week, participants reduced liver fat by 4.6% over 9 months.[6] Similarly, a randomized controlled trial in participants with NAFLD reported that two to three sessions of supervised nordic walking per week (performed at 60–75% of VO2max for 30–60 minutes) combined with a dietary intervention reduced liver fat by 7.6%.[7] Finally, evidence from a couple of meta-analyses indicate that exercise interventions (without dietary interventions in most studies) involving roughly three sessions of 30–60 minutes of aerobic exercise per week for 12 weeks significantly reduced liver fat.[5][8] One of these meta-analyses reported an average reduction in liver fat of 3.3%.[5]

In sum, less demanding exercise interventions than used in the summarized study seem to be able to promote similar reductions in liver fat. At the moment, there doesn’t appear to be a clear relationship between reductions in liver fat and the weekly frequency and volume of exercise in people with NAFLD.[9]

Exercise type may also play a role. The present study used prolonged moderate-intensity aerobic exercise, which may not suit many people’s preferences.

A 2017 meta-analysis reported that aerobic and resistance exercise interventions produce similar reductions in liver fat in people with NAFLD, even though energy expenditure tended to be lower in resistance exercise interventions.[8]

Additionally, the following results have been reported in trials that performed head-to-head comparisons between different exercise interventions in participants with NAFLD:

  • 4 weeks of either moderate-intensity aerobic exercise (55% of VO2max) or high-intensity interval aerobic exercise (repeated cycles of 4 minutes at 80% of VO2max followed by 3 minutes at 50% of VO2max), which were matched for energy expenditure (about 400 kcal per session), produced similar reductions in liver fat.[10]
  • 6 months of either moderate-intensity aerobic exercise (45%–55% of maximum predicted heart rate for 150 minutes per week) or vigorous aerobic exercise (65%–80% of maximum predicted heart rate for 150 minutes per week) produced similar reductions in liver fat.[11]
  • 4 months of either aerobic exercise (60%–65% of heart rate reserve for 180 minutes per week) or resistance exercise (three full-body sessions per week consisting of 9 exercises performed for 3 sets of 10 repetitions using 70%–80% of 1-repetition maximum) produced similar reductions in liver fat.[12]
  • 3 months of either aerobic exercise (60%–75% of VO2max for 180 minutes per week) or resistance exercise (three full-body sessions per week consisting of 10 exercises performed for 2 sets of 8–12 repetitions to fatigue each) produced similar reductions in liver fat.[13]

Although head-to-head comparisons are sparse, the available evidence indicates that different types of exercise have similar effects on reducing liver fat. Further research is needed to clarify the most effective form of exercise for reducing liver fat, as well as the ideal amount of exercise. Moreover, it remains unclear whether combining aerobic and resistance exercise is superior to either mode of exercise alone for reducing liver fat.[9]

However, as it stands, the available evidence indicates that various types of exercise interventions can be used to reduce liver fat. Thus, the general recommendation to accumulate at least 150 minutes of moderate-intensity or 75 minutes of high-intensity exercise per week is a suitable target for most people.[9] Following this recommendation, the mode, frequency, and duration of exercise should be customized to the individual’s preferences and goals to maximize adherence.

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This Study Summary was published on March 1, 2023.

References

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  2. ^Oh S, Tsujimoto T, Kim B, Uchida F, Suzuki H, Iizumi S, Isobe T, Sakae T, Tanaka K, Shoda JWeight-loss-independent benefits of exercise on liver steatosis and stiffness in Japanese men with NAFLD.JHEP Rep.(2021-Jun)
  3. ^Shelby Sullivan, Erik P Kirk, Bettina Mittendorfer, Bruce W Patterson, Samuel KleinRandomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver diseaseHepatology.(2012 Jun)
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  7. ^Cheng S, Ge J, Zhao C, Le S, Yang Y, Ke D, Wu N, Tan X, Zhang X, Du X, Sun J, Wang R, Shi Y, Borra RJH, Parkkola R, Wiklund P, Lu DEffect of aerobic exercise and diet on liver fat in pre-diabetic patients with non-alcoholic-fatty-liver-disease: A randomized controlled trial.Sci Rep.(2017-Nov-21)
  8. ^Hashida R, Kawaguchi T, Bekki M, Omoto M, Matsuse H, Nago T, Takano Y, Ueno T, Koga H, George J, Shiba N, Torimura TAerobic vs. resistance exercise in non-alcoholic fatty liver disease: A systematic review.J Hepatol.(2017-Jan)
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  11. ^Zhang HJ, He J, Pan LL, Ma ZM, Han CK, Chen CS, Chen Z, Han HW, Chen S, Sun Q, Zhang JF, Li ZB, Yang SY, Li XJ, Li XYEffects of Moderate and Vigorous Exercise on Nonalcoholic Fatty Liver Disease: A Randomized Clinical Trial.JAMA Intern Med.(2016-Aug-01)
  12. ^Bacchi E, Negri C, Targher G, Faccioli N, Lanza M, Zoppini G, Zanolin E, Schena F, Bonora E, Moghetti PBoth resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial).Hepatology.(2013-Oct)
  13. ^Lee S, Bacha F, Hannon T, Kuk JL, Boesch C, Arslanian SEffects of aerobic versus resistance exercise without caloric restriction on abdominal fat, intrahepatic lipid, and insulin sensitivity in obese adolescent boys: a randomized, controlled trial.Diabetes.(2012-Nov)