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Cited by 70Liver Disease Diagnosis and TreatmentNutritional Studies and DietDiet, Metabolism, and Disease

Diet and physical exercise as key players to tackle MASLD through improvement of insulin resistance and metabolic flexibility

Open access
Mambrini, Sara Paola, Grillo, Antonio, Colosimo, Santo, Zarpellon, Francesco, Pozzi, Giorgia, Furlan, Davide, Amodeo, Gabriele, Bertoli, Simona·2024·Frontiers in Nutrition
DOI 10.3389/fnut.2024.1426551PMC PMC11370663
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Abstract

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has emerged as a prevalent health concern, encompassing a wide spectrum of liver-related disorders. Insulin resistance, a key pathophysiological feature of MASLD, can be effectively ameliorated through dietary interventions. The Mediterranean diet, rich in whole grains, fruits, vegetables, legumes, and healthy fats, has shown promising results in improving insulin sensitivity. Several components of the Mediterranean diet, such as monounsaturated fats and polyphenols, exert anti-inflammatory and antioxidant effects, thereby reducing hepatic steatosis and inflammation. Furthermore, this dietary pattern has been associated with a higher likelihood of achieving MASLD remission. In addition to dietary modifications, physical exercise, particularly resistance exercise, plays a crucial role in enhancing metabolic flexibility. Resistance exercise training promotes the utilization of fatty acids as an energy source. It enhances muscle glucose uptake and glycogen storage, thus reducing the burden on the liver to uptake excess blood glucose. Furthermore, resistance exercise stimulates muscle protein synthesis, contributing to an improved muscle-to-fat ratio and overall metabolic health. When implemented synergistically, the Mediterranean diet and resistance exercise can elicit complementary effects in combating MASLD. Combined interventions have demonstrated additive benefits, including greater improvements in insulin resistance, increased metabolic flexibility, and enhanced potential for MASLD remission. This underscores the importance of adopting a multifaceted approach encompassing dietary modifications and regular physical exercise to effectively manage MASLD. This narrative review explores the biological mechanisms of diet and physical exercise in addressing MASLD by targeting insulin resistance and decreased metabolic flexibility.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that the Mediterranean diet and physical exercise, especially resistance exercise, can improve insulin resistance and metabolic flexibility in MASLD. It synthesizes mechanistic and clinical evidence suggesting combined lifestyle intervention may promote MASLD remission and liver-fat reduction.

Key findings

  • MASLD affects approximately 25% of the global population; recommended weight loss is 7–10%, while >10% weight loss is associated with superior resolution of MASLD/MASH and regression of fibrosis and inflammation.
  • In a reviewed analysis of exercise trials, aerobic exercise protocols reduced hepatic steatosis in 91.7% of 24 protocols from 18 articles, while resistance exercise reduced hepatic steatosis in 85.7% of 7 protocols from 7 studies, including 5 randomized controlled trials.
  • Resistance exercise improved steatosis with modest BMI/ALT changes and, in three protocols, without significant weight loss; MR spectroscopy showed intrahepatic lipid reductions of 13%, 3%, and 25% from baseline in three studies.
  • A crossover randomized controlled trial in 12 non-diabetic subjects with biopsy-proven MASLD found that a Mediterranean diet reduced hepatic steatosis and improved insulin sensitivity even without weight loss; a separate review of nine dietary patterns found the Mediterranean diet most efficacious for postprandial hyperglycaemia and insulin sensitivity at equivalent body weight.

Methods

  • Narrative review exploring biological mechanisms by which diet and physical exercise address MASLD by targeting insulin resistance and decreased metabolic flexibility.
  • Evidence is synthesized from prior reviews, clinical trials, and mechanistic studies, including exercise protocols for hepatic steatosis and dietary-pattern studies; no primary data collection or systematic meta-analysis is reported.

Limitations

  • The paper states that further research is needed on the long-term effects of resistance exercise and its mechanisms in improving hepatic steatosis, and that the exact impact of BMR on MASLD needs further investigation.
  • The paper states that the optimal exercise protocol remains unclear, including recommended frequency, intensity, and duration, and that comparison of exercise types based on energy consumption has not yet been conducted.
  • Evident from the text: as a narrative review, it lacks a stated systematic search strategy, formal risk-of-bias assessment, or meta-analytic synthesis, and it relies partly on animal-model and in vitro findings that the authors note may not directly translate to humans.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fnut.2024.1426551

Cites

114 of 114 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 103 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Reduced metabolic flexibility remains a less explored mechanism in MASLD.

    “While insulin resistance has been considered one of the most relevant pathogenetic feature of MASLD and the driver for the progression of liver inflammation (11), reduced metabolic flexibility remains a less explored mechanism (12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Colosimo, 2023, Insulin resistance and metabolic flexibility as drivers of liver and cardiac disease in T2DM, Diabetes Res Clin Pract source

      Not checked in the free run.

  • Premisecitation

    Modifications in lean mass and adipose tissue mass are the primary influencers of BMR.

    “According to existing literature, modifications in lean mass and adipose tissue mass are recognized as the primary influencers of BMR (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Carneiro, 2016, Is obesity associated with altered energy expenditure?, Adv Nutr source

      Not checked in the free run.

  • Premisecitation

    The synergistic benefits of weight loss are contingent on the adoption of a combined dietary and exercise approach.

    “Notably, the synergistic benefits of weight loss are contingent on the adoption of a combined dietary and exercise approach (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Bischoff, 2020, ESPEN practical guideline: clinical nutrition in liver disease, Clin Nutr source

      Not checked in the free run.

  • Premisecitation

    Changes in factors influencing basal metabolism are causatively associated with increased susceptibility to specific clinical conditions, such as obesity, thereby raising the risk of developing MASLD.

    “The factors that influence basal metabolism have demonstrated their crucial role, as changes in these parameters have been causatively associated with an increased susceptibility to specific clinical conditions, such as obesity, thereby raising the risk of developing MASLD (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Astrup, 1999, Meta-analysis of resting metabolic rate in formerly obese subjects, Am J Clin Nutr source

      Not checked in the free run.

  • Premisecitation

    Resmetirom is superior to placebo with respect to MASH resolution and improvement in liver fibrosis in a stage 3 trial.

    “Resmetirom, an oral, liver-directed, thyroid hormone receptor beta (THR-β)–selective agonist, were superior to placebo with respect to MASH resolution and improvement in liver fibrosis in a stage 3 trial (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Harrison, 2024, A phase 3, randomized, controlled trial of Resmetirom in NASH with liver fibrosis, N Engl J Med source

      Not checked in the free run.

  • May combine two claims. 32
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Premisecitation

    Weight loss exceeding 10% has superior efficacy in resolving MASLD and MASH, exhibiting regression of fibrosis and inflammation.

    “Weight loss exceeding 10% has demonstrated superior efficacy in resolving MASLD and MASH, exhibiting regression of fibrosis and inflammation (6, 7).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Vilar-Gomez, 2015, Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis, Gastroenterology source

      Not checked in the free run.

    • cites [7] Friedman, 2018, Mechanisms of NAFLD development and therapeutic strategies, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In individuals who lead a sedentary lifestyle, BMR accounts for 60 to 70% of total energy expenditure, whereas in those who regularly engage in physical activities, this percentage decreases to approximately 50%.

    “In individuals who lead a sedentary lifestyle, BMR accounts for a significant proportion, ranging from 60 to 70% of the total energy expenditure, whereas in those who regularly engage in physical activities, this percentage decreases to approximately 50% (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Blasco, 2015, Resting energy expenditure; assessment methods and applications, Nutr Hosp

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Sufficient protein intake is considered crucial for maintaining lean mass in low-calorie dietary regimens.

    “For instance, sufficient protein intake is considered crucial for maintaining lean mass in low-calorie dietary regimens (21, 22).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Bi, 2019, Basal metabolic rate and body composition predict habitual food and macronutrient intakes: gender differences, Nutrients source

      Not checked in the free run.

    • cites [22] Stiegler, 2006, The role of diet and exercise for the maintenance of fat-free mass and resting metabolic rate during weight loss, Sports Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After periods of calorie restriction, BMR may exhibit an adaptive response known as "metabolic adaptation," which negatively affects the rate of BMR and predisposes individuals to a higher risk of weight regain.

    “Conversely, divergent studies have revealed that after periods of calorie restriction, BMR may exhibit an adaptive response known as “metabolic adaptation,” which negatively affects the rate of BMR and predisposes individuals to a higher risk of weight regain (17–19).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Astrup, 1999, Meta-analysis of resting metabolic rate in formerly obese subjects, Am J Clin Nutr source

      Not checked in the free run.

    • cites [18] Martínez-Gómez, 2022, Metabolic adaptations to weight loss: a brief review, J Strength Cond Res source

      Not checked in the free run.

    • cites [19] Marchesini, 2004, Weight cycling in treatment-seeking obese persons: data from the QUOVADIS study, Int J Obes Relat Metab Disord source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A targeted weight reduction of 7-10% is effective in mitigating lipid accumulation, enhancing metabolic flexibility, and ameliorating insulin resistance.

    “As far as weight loss for the treatment of MASLD is concerned, the recommendation is a targeted weight reduction of 7–10%, a measure found to be effective in mitigating lipid accumulation, enhancing metabolic flexibility, and ameliorating insulin resistance (6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Vilar-Gomez, 2015, Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin resistance is one of the most relevant pathogenetic features of MASLD and the driver for progression of liver inflammation.

    “While insulin resistance has been considered one of the most relevant pathogenetic feature of MASLD and the driver for the progression of liver inflammation (11), reduced metabolic flexibility remains a less explored mechanism (12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Bugianesi, 2005, Insulin resistance: a metabolic pathway to chronic liver disease, Hepatology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MASLD is a disease spectrum spanning from simple excess triacylglycerol accumulation within hepatocytes (steatosis) to inflammation (MASH), cirrhosis and hepatocellular carcinoma.

    “MASLD is a disease spectrum spanning from simple excess triacylglycerol (TAG) accumulation within the hepatocytes (steatosis) to inflammation (metabolic dysfunction-associated steatohepatitis, MASH), cirrhosis and hepatocellular carcinoma (HCC) (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Marjot, 2020, Nonalcoholic fatty liver disease in adults: current concepts in etiology, outcomes, and management, Endocr Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Very short or low-intensity exercises may be insufficient for improving hepatic steatosis, emphasizing the importance of exercise energy consumption.

    “Also, very short or low-intensity exercises may be insufficient for improving hepatic steatosis, emphasizing the importance of exercise energy consumption (68, 69).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [68] Fealy, 2012, Short-term exercise reduces markers of hepatocyte apoptosis in nonalcoholic fatty liver disease, J Appl Physiol (1985) source

      Not checked in the free run.

    • cites [69] Keating, 2015, Effect of aerobic exercise training dose on liver fat and visceral adiposity, J Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One study did not show improvements in hepatic steatosis through resistance exercise; longer duration (32 weeks) and significant increase in body weight may have influenced results.

    “One study did not show improvements in hepatic steatosis through resistance exercise (82). The longer duration (32 weeks) and significant increase in body weight in that study may have influenced the results.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Slentz, 2011, Effects of aerobic vs. resistance training on visceral and liver fat stores, liver enzymes, and insulin resistance by HOMA in overweight adults from STRRIDE AT/RT, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Moderate-intensity aerobic exercise for 40 min over 12 weeks was the typical protocol and led to improvements in BMI and serum alanine aminotransferase levels.

    “Moderate-intensity aerobic exercise for a duration of 40 min over a 12-week period was the typical protocol. Aerobic exercise led to improvements in BMI and serum alanine aminotransferase levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Hashida, 2017, Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: a systematic review, J Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aerobic exercise can decrease serum levels of resistin and increase levels of high molecular weight adiponectin.

    “Studies have shown that aerobic exercise can decrease serum levels of resistin and increase levels of high molecular weight adiponectin, indicating potential benefits for individuals with conditions like hypertension and MASLD (73–75).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [73] Aghapour, 2013, Effect of six-week aerobic exercise on Chemerin and Resistin concentration in hypertensive postmenopausal women, Electron Physician source

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    • cites [74] Haus, 2013, Improved hepatic lipid composition following short-term exercise in nonalcoholic fatty liver disease, J Clin Endocrinol Metab source

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    • cites [75] Nikseresht, 2014, Inflammatory markers and adipocytokine responses to exercise training and detraining in men who are obese, J Strength Cond Res source

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  • May combine two claims.

    Premisecitation

    Resistance exercise specifically promotes hypertrophy in type II muscle fibers, while not significantly affecting type I fibers.

    “Resistance exercise has been found to specifically promote hypertrophy in type II muscle fibers, while not significantly affecting type I fibers.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [84] Lillioja, 1987, Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man, J Clin Invest source

      Not checked in the free run.

    • cites [85] Verdijk, 2009, Skeletal muscle hypertrophy following resistance training is accompanied by a fiber type-specific increase in satellite cell content in elderly men, J Gerontol A Biol Sci Med Sci source

      Not checked in the free run.

    • cites [86] Gallagher, 2013, Effects of an acute bout of resistance exercise on fiber-type specific to GLUT4 and IGF-1R expression, Appl Physiol Nutr Metab source

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    • cites [87] Oh, 2007, Exercise type and muscle fiber specific induction of caveolin-1 expression for insulin sensitivity of skeletal muscle, Exp Mol Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aerobic exercise upregulates uncoupling protein-1 and peroxisome proliferator-activated receptor gamma, which further enhance lipolysis in adipose tissues.

    “Aerobic exercise also upregulates certain proteins, such as uncoupling protein-1 and peroxisome proliferator-activated receptor gamma (71), which further enhance lipolysis in adipose tissues (72).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [71] Petridou, 2007, Long-term exercise increases the DNA binding activity of peroxisome proliferator-activated receptor gamma in rat adipose tissue, Metabolism source

      Not checked in the free run.

    • cites [72] Ricquier, 2005, Respiration uncoupling and metabolism in the control of energy expenditure, Proc Nutr Soc source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resistance exercise increases expression of GLUT-4 in type II fibers and enhances intracellular insulin sensitivity.

    “Additionally, resistance exercise has been shown to increase the expression of GLUT-4 in type II fibers and enhance intracellular insulin sensitivity (84–87).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [84] Lillioja, 1987, Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man, J Clin Invest source

      Not checked in the free run.

    • cites [85] Verdijk, 2009, Skeletal muscle hypertrophy following resistance training is accompanied by a fiber type-specific increase in satellite cell content in elderly men, J Gerontol A Biol Sci Med Sci source

      Not checked in the free run.

    • cites [86] Gallagher, 2013, Effects of an acute bout of resistance exercise on fiber-type specific to GLUT4 and IGF-1R expression, Appl Physiol Nutr Metab source

      Not checked in the free run.

    • cites [87] Oh, 2007, Exercise type and muscle fiber specific induction of caveolin-1 expression for insulin sensitivity of skeletal muscle, Exp Mol Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Elevated plasma concentrations of T4 are associated with increased BMR.

    “A recent study demonstrated that elevated plasma concentrations of T4 were associated with increased BMR.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Johnstone, 2005, Factors influencing variation in basal metabolic rate include fat-free mass, fat mass, age, and circulating thyroxine but not sex, circulating leptin, or triiodothyronine, Am J Clin Nutr source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Resistance exercise may have distinct therapeutic characteristics compared to aerobic exercise in MASLD patients, as it showed modest changes in BMI and demonstrated steatosis improvement independent of body weight reduction.

    “Resistance exercise may have distinct therapeutic characteristics compared to aerobic exercise in MASLD patients, as it showed modest changes in BMI and demonstrated steatosis improvement independent of body weight reduction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Hashida, 2017, Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: a systematic review, J Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Irisin is released by skeletal muscles and increases thermogenesis and energy expenditure by promoting browning of subcutaneous adipocytes.

    “Irisin is released by skeletal muscles and has been shown to increase thermogenesis and energy expenditure by promoting the browning of subcutaneous adipocytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Boström, 2012, A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis, Nature source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Exercise, height, general weight, age, and circulating thyroid hormones are influential in modulating BMR.

    “Additional factors that have emerged in the literature as influential in modulating BMR include exercise, height, general weight, age, and circulating thyroid hormones (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Johnstone, 2005, Factors influencing variation in basal metabolic rate include fat-free mass, fat mass, age, and circulating thyroxine but not sex, circulating leptin, or triiodothyronine, Am J Clin Nutr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resistance exercise significantly increased circulating irisin levels, while aerobic exercise did not produce the same effect.

    “They found that resistance exercise significantly increased circulating irisin levels, while aerobic exercise did not produce the same effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Kim, 2016, Effect of aerobic training and resistance training on circulating irisin level and their association with change of body composition in overweight/obese adults: a pilot study, Physiol Res source

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  • May combine two claims.

    Premisecitation

    High-intensity interval training (HIIT) demonstrated reductions in whole-body fat mass, serum alanine aminotransferase levels, and hepatic lipids.

    “However, a study on high-intensity interval training (HIIT) demonstrated reductions in whole-body fat mass, serum alanine aminotransferase levels, and hepatic lipids.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Hallsworth, 2015, Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: a randomized controlled trial, Clin Sci (Lond) source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Disruptions to metabolic flexibility, such as in MASLD, can impair the body's ability to efficiently switch between glucose and lipid oxidation, leading to accumulation of lipids in non-adipose tissues like the liver and exacerbating disease progression.

    “Disruptions to this metabolic flexibility, such as in metabolic disorders like MASLD, can impair the body ability to efficiently switch between glucose and lipid oxidation. This can lead to the accumulation of lipids in non-adipose tissues like the liver, exacerbating disease progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Resistance physical activity is essential for increasing energy supply to tissues and improving metabolic flexibility.

    “Resistance physical activity is therefore essential for increasing energy supply to tissues and improving metabolic flexibility.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    As exercise intensity increases, there is greater reliance on glucose oxidation through oxidative phosphorylation, while anaerobic glycolysis becomes the predominant pathway during higher intensity exercise.

    “As exercise intensity increases, there is a greater reliance on glucose oxidation through oxidative phosphorylation, while anaerobic glycolysis becomes the predominant pathway during higher intensity exercise (105).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] van Loon, 2001, The effects of increasing exercise intensity on muscle fuel utilisation in humans, J Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Weight loss interventions improve serum liver enzymes, reduce hepatic lipid accumulation, and alleviate liver inflammation.

    “This is evidenced by enhanced serum liver enzymes, reduced hepatic lipid accumulation, and alleviation of liver inflammation following weight loss interventions (100).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [100] Papakonstantinou, 2022, Effects of diet, lifestyle, Chrononutrition and alternative dietary interventions on postprandial Glycemia and insulin resistance, Nutrients source

      Not checked in the free run.

    • cites [101] 2024, EASL-EASD-EASO clinical practice guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD), J Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During acute exercise, the release of free fatty acids from adipose tissue is primarily driven by increased levels of catecholamines, with abdominal subcutaneous white adipose tissue being the main source.

    “During acute exercise, the release of free fatty acids (FFAs) from adipose tissue is primarily driven by increased levels of catecholamines, with abdominal subcutaneous white adipose tissue (WAT) being the main source (108).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Arner, 2010, Adipocyte turnover: relevance to human adipose tissue morphology, Diabetes source

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  • May combine two claims.

    Premisecitation

    These metabolic shifts occur independently of insulin, as circulating insulin levels remain suppressed during exercise, and the contribution of fatty acid oxidation to energy production decreases proportionally.

    “These metabolic shifts occur independently of insulin, as circulating insulin levels remain suppressed during exercise, and the contribution of fatty acid oxidation to energy production decreases proportionally (106, 107).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [106] Wasserman, 1994, Exercise in individuals with IDDM, Diabetes Care source

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    • cites [107] Romijn, 1993, Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration, Am J Phys source

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  • May combine two claims.

    Premisecitation

    Carbohydrate sources prevalent in the Mediterranean diet, primarily legumes and whole grains, exhibit efficacy in postprandial hyperglycaemia and enhance insulin sensitivity.

    “Focusing on the carbohydrate sources prevalent in the Mediterranean diet, these primarily consist of legumes and whole grains. These components exhibit efficacy in postprandial hyperglycaemia, which increase more gradually over time, and enhance insulin sensitivity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Papakonstantinou, 2022, Effects of diet, lifestyle, Chrononutrition and alternative dietary interventions on postprandial Glycemia and insulin resistance, Nutrients source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mechanistic underpinnings of these fatty acid effects involve downregulation of SREBP-1c and activation of PPARα.

    “The mechanistic underpinnings involve the downregulation of SREBP-1c and activation of PPARα (98).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Sekiya, 2003, Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression, Hepatology source

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  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Resistance exercise training promotes the utilization of fatty acids as an energy source.

    “Resistance exercise training promotes the utilization of fatty acids as an energy source.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Soluble fibre attenuates pronounced glycaemic peaks characteristic of a Western diet, thereby mitigating oxidative stress, preserving pancreatic beta cell integrity, delaying gastric emptying, and correlating with reduced insulin requirements.

    “Soluble fibre attenuates the pronounced glycaemic peaks characteristic of a Western diet, thereby mitigating oxidative stress, preserving pancreatic beta cell integrity, delaying gastric emptying, and correlating with reduced insulin requirements (100).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Papakonstantinou, 2022, Effects of diet, lifestyle, Chrononutrition and alternative dietary interventions on postprandial Glycemia and insulin resistance, Nutrients source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Impaired metabolic flexibility impacts the body's ability to properly adjust to different physiological conditions, including exercise.

    “Impaired metabolic flexibility impacts the body ability to properly adjust to different physiological conditions, including exercise.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Resistance exercise enhances muscle glucose uptake and glycogen storage, thus reducing the burden on the liver to uptake excess blood glucose.

    “It enhances muscle glucose uptake and glycogen storage, thus reducing the burden on the liver to uptake excess blood glucose.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These fatty acids have demonstrated efficacy in enhancing insulin sensitivity, ameliorating steatohepatitis, and reducing intrahepatic triglyceride content.

    “Moreover, these fatty acids have demonstrated efficacy in enhancing insulin sensitivity, ameliorating steatohepatitis, and reducing intrahepatic triglyceride content.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Sekiya, 2003, Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression, Hepatology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blocking β-adrenergic receptors in abdominal subcutaneous WAT reduces lipolysis, demonstrating the role of WAT in metabolic flexibility during exercise.

    “Studies blocking β-adrenergic receptors in abdominal subcutaneous WAT have demonstrated the role of WAT in metabolic flexibility during exercise by reducing lipolysis (109).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Arner, 1990, Adrenergic regulation of lipolysis in situ at rest and during exercise, J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Combined interventions have demonstrated additive benefits, including greater improvements in insulin resistance, increased metabolic flexibility, and enhanced potential for MASLD remission.

    “Combined interventions have demonstrated additive benefits, including greater improvements in insulin resistance, increased metabolic flexibility, and enhanced potential for MASLD remission.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a crossover randomized controlled trial of twelve non-diabetic subjects with biopsy-proven MASLD, adherence to the Mediterranean diet led to a reduction in hepatic steatosis and an improvement in insulin sensitivity even in the absence of weight loss.

    “Notably, the findings demonstrated that, even in the absence of weight loss, adherence to the Mediterranean diet led to a reduction in hepatic steatosis and an improvement in insulin sensitivity (102).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Ryan, 2013, The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease, J Hepatol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Insulin resistance involves various tissues and organs, with the liver being a key organ where the shift from metabolic flexibility to inflexibility occurs.

    “Insulin resistance involves various tissues and organs, with the liver being a key organ where the shift from metabolic flexibility to inflexibility occurs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    During exercise and under other changing conditions, decreased metabolic flexibility can compromise the body's ability to handle different substrates.

    “During exercise and under other changing conditions, decreased metabolic flexibility can compromise the body ability to handle different substrates.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Resistance exercise stimulates muscle protein synthesis, contributing to an improved muscle-to-fat ratio and overall metabolic health.

    “Furthermore, resistance exercise stimulates muscle protein synthesis, contributing to an improved muscle-to-fat ratio and overall metabolic health.”
    Quote in the paperNot a substantial claim
39 of 39

  • The paper relies on this without support.

    Lifestyle changes aimed at weight loss remain the mainstay of MASLD treatment in the general population.

    “Nonetheless, lifestyle changes aimed at weight loss remain the mainstay of MASLD treatment in general population.”

  • The paper relies on this without support.

    The primary approach to managing MASLD involves substantial weight loss and intensive reduction of cardiovascular risk factors.

    “The primary approach to managing the disease involves substantial weight loss and intensive reduction of cardiovascular risk factors.”

  • The paper relies on this without support.

    MASLD carries a burden of morbidity and mortality, primarily due to liver-related complications, but more significantly due to unfavorable cardiovascular events.

    “MASLD carries a burden of morbidity and mortality, primarily due to liver-related complications, but more significantly due to unfavorable cardiovascular events.”

  • The paper relies on this without support.

    PUFAs influence glucose metabolism by binding and stimulating GPCRs such as GPR120, leading to increased GLP-1 secretion and downstream insulin release and glucose uptake.

    “PUFAs also play a significant influence on glucose metabolism by binding and stimulating G-protein-coupled receptors (GPCRs), such as GPR120.”

  • The paper relies on this without support.

    Increased energy demand during aerobic exercise upregulates PPAR-α activity within muscle cells, and high PPARα activity in skeletal muscle up-regulates delivery of fatty acids from WAT to skeletal muscle.

    “On the other hand, the increased energy demand during aerobic exercise can upregulate the activity of PPAR-α within muscle cells. As discussed in the section 1.7, high PPARα activity in skeletal muscle up-regulates the delivery of fatty acids from WAT to skeletal muscle.”

  • The paper relies on this without support.

    Strategies aimed at modifying substrate metabolism or metabolic flexibility do not replicate the same energy expenditure or demand observed during exercise.

    “Notably, these strategies do not replicate the same energy expenditure or demand observed during exercise.”
6 of 6

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Authors
Mambrini, S. P., Grillo, A., Colosimo, S., Zarpellon, F., Pozzi, G., Furlan, D., Amodeo, G., & Bertoli, S.
Affiliations
  • IRCCS Istituto Auxologico Italiano (IT)
  • University of Milan (IT)
Corresponding author
Colosimo, Santo
ORCID
Venue
Frontiers in Nutrition
Publisher
Frontiers Media SA
Published
2024-08-20
Volume
11
Pages
1426551-1426551
ISSN
2296-861X (ISSN-L)
DOI
10.3389/fnut.2024.1426551
PMC
PMC11370663
OpenAlex
W4401977029
Semantic Scholar
b8454ca2475b3f28c7c2579bb3d1d03fa66c9acb
Cited by
70
References
114
Citations by year
2026: 32 · 2025: 36 · 2024: 2
FWCI
4.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Nutrition (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Keywords
non-alcoholic fatty liver disease, insulin resistance, metabolic flexibility, Mediterranean diet, resistance training, dietary intervention, hepatic steatosis, polyphenols, monounsaturated fatty acids, muscle glucose uptake, muscle protein synthesis, fatty acid utilization

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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