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Cited by 43Regulation of Appetite and ObesityNutrition, Genetics, and DiseaseBody Composition Measurement Techniques

Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review

Open access
Theodorakis, Nikolaos, Kreouzi, Magdalini, Pappas, Andreas, Nikolaou, Maria·2024·International Journal of Molecular Sciences
DOI 10.3390/ijms252413438PMC PMC11676201
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Abstract

The global rise in obesity underscores the need for effective weight management strategies that address individual metabolic and hormonal variability, moving beyond the simplistic “calories in, calories out” model. Body types—ectomorph, mesomorph, and endomorph—provide a framework for understanding the differences in fat storage, muscle development, and energy expenditure, as each type responds uniquely to caloric intake and exercise. Variability in weight outcomes is influenced by factors such as genetic polymorphisms and epigenetic changes in hormonal signaling pathways and metabolic processes, as well as lifestyle factors, including nutrition, exercise, sleep, and stress. These factors impact the magnitude of lipogenesis and myofibrillar protein synthesis during overfeeding, as well as the extent of lipolysis and muscle proteolysis during caloric restriction, through complex mechanisms that involve changes in the resting metabolic rate, metabolic pathways, and hormonal profiles. Precision approaches, such as nutrigenomics, indirect calorimetry, and artificial-intelligence-based strategies, can potentially leverage these insights to create individualized weight management strategies aligned with each person’s unique metabolic profile. By addressing these personalized factors, precision nutrition offers a promising pathway to sustainable and effective weight management outcomes. The main objective of this review is to examine the metabolic and hormonal adaptations driving variability in weight management outcomes and explore how precision nutrition can address these challenges through individualized strategies.

AI snapshot

Written from the paper’s full text.

TL;DR

This state-of-the-art narrative review argues that weight-management variability is driven by individual metabolic and hormonal adaptations beyond the “calories in, calories out” model, including adaptive thermogenesis, appetite hormones, thyroid/SNS/leptin changes, and genetic, epigenetic, and lifestyle factors. It proposes precision nutrition using nutrigenomics, indirect calorimetry, and AI/ML to tailor interventions to each person’s metabolic profile.

Key findings

  • The review reports that global age-standardized obesity prevalence rose from 4.6% in 1980 to 14.0% in 2019, and it critiques calorie-counting because food energy labels may vary by up to 20% under regulatory standards and discrepancies can reach 60% in practice.
  • Caloric restriction triggers adaptive responses: a 10% weight reduction decreased total energy expenditure by 6 ± 3 kcal/kg fat-free mass/day in non-obese subjects and 8 ± 5 kcal/kg/day in obese subjects (both p < 0.001); in a six-year follow-up of “The Biggest Loser” participants, initial weight loss was 58.3 ± 24.9 kg with RMR reduced by 610 ± 483 kcal/day (p = 0.0004), and RMR remained 704 ± 427 kcal/day below baseline (p < 0.0001) despite weight regain. After mean 13.5 ± 0.5 kg weight loss, leptin, PYY, CCK, and insulin decreased while ghrelin and gastric inhibitory polypeptide increased (p < 0.001), persisting at one year for leptin and ghrelin (p < 0.001).
  • Overfeeding (+1180 kcal/day) produced significant increases in body and fat mass (1.6 kg and 1.3 kg, respectively) only after 28 days (p < 0.05), with postprandial glucose and insulin stable at 5 days but modestly increased by 28 days (p < 0.05).
  • Precision-nutrition trials showed mixed specificity: DIETFITS (609 overweight adults) found no significant 12-month weight difference between healthy low-fat (−5.3 kg) and healthy low-carbohydrate (−6.0 kg) diets (mean difference 0.7 kg; 95% CI, −0.2 to 1.6; p = 0.20), with no diet–genotype (p = 0.20) or diet–insulin (p = 0.47) interaction; NOW (n = 140) found only the nutrigenomics-guided group significantly reduced total fat intake from 36.0% ± 4.8% to 30.2% ± 8.7% kcal (p = 0.02); PREDICT1 (1002 UK and 100 US participants) reported postprandial triglyceride, glucose, and insulin coefficients of variation of 103%, 68%, and 59%, with gut microbiome explaining 7.1% of postprandial lipemia variance versus 3.6% for meal macronutrients, and ML models predicting triglyceride (r = 0.47, p < 0.001) and glycemic (r = 0.77, p < 0.001) responses. An indirect-calorimetry meta-analysis of eight RCTs (n = 911) found higher mean daily energy intake (622 kcal/day, p < 0.00001) and reduced short-term mortality (RR = 0.77; 95% CI 0.60 to 0.98; I² = 3%, p = 0.03) versus predictive equations.

Methods

  • State-of-the-art narrative literature review synthesizing current knowledge on metabolic and hormonal mechanisms underlying individual variability in weight management and precision approaches.
  • Literature search in PubMed and Scopus up to 1 November 2024 using keywords and MeSH terms including weight management, weight loss, weight gain, metabolism, hormonal variability, precision nutrition, obesity, caloric restriction, overfeeding, somatotypes, and adaptive thermogenesis, with Boolean operators.
  • Inclusion criteria were reviews or original research articles in English up to 1 November 2024, focusing on metabolic/hormonal mechanisms driving individual variability in weight outcomes or precision nutrition/personalized approaches; articles were screened by title/abstract, full-text reviewed, supplemented by manual reference-list review, and findings were synthesized.

Limitations

  • The paper states limitations including heterogeneity in study designs and reliance on observational or small-scale trials limiting causal inference and generalizability; inconsistent definitions/measurement of BMR, hormonal fluctuations, and energy expenditure; population bias toward obesity or metabolic syndrome with limited representation of athletes, older adults with sarcopenia, and diverse ethnic backgrounds; inadequate control for confounders such as sleep quality, stress, and dietary composition; underexplored environmental and epigenetic influences; precision-medicine approaches that are mostly pilot-scale, lack validation in larger diverse cohorts, and have high costs; and a focus on short-term outcomes without sufficient long-term sustainability data.
  • Evident from the text: as a narrative review, it does not report a systematic protocol, risk-of-bias assessment, or quantitative synthesis; several cited mechanistic findings come from animal or cell models (e.g., mouse mTORC1 leucine sensitivity, T2DM mouse resistance-exercise pathway), and one cited human supplement finding states that leucine supplementation was not shown to significantly impact body composition and physical performance.

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Integrity signals

Registry

Crossref · 10.3390/ijms252413438

Cites

107 of 107 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 285 cited sources checked · 0 supported · 0 flagged

  • Premisereasoning

    Low-GI foods like whole grains may lead to lower total calorie absorption because some of their fiber and resistant starches pass through the digestive tract partially undigested.

    “Additionally, low-GI foods like whole grains may lead to lower total calorie absorption, as some of their fiber and resistant starches pass through the digestive tract partially undigested.”
    Quote in the paperNot a substantial claim
  • Premisereasoning

    The carbohydrate-insulin model proposes that not just calorie quantity but also the type of calories plays a crucial role in weight gain.

    “Unlike the “calories in, calories out” model, the carbohydrate–insulin model suggests that it is not just calorie quantity but also the type of calories that plays a crucial role.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    A 10% weight reduction led to a significant decrease in total energy expenditure (6 ± 3 kcal/kg fat-free mass/day in non-obese subjects and 8 ± 5 kcal/kg/day in obese subjects, both p < 0.001).

    “The findings revealed that a 10% weight reduction led to a significant decrease in total energy expenditure (6 ± 3 kcal/kg fat-free mass/day in non-obese subjects and 8 ± 5 kcal/kg/day in obese subjects, both p < 0.001) [28].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Leibel, 1995, Changes in energy expenditure resulting from altered body weight, N. Engl. J. Med. source

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    Ghrelin rises during caloric restriction.

    “Ghrelin, primarily produced by the stomach, rises during caloric restriction [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Zekri, Y., Flamant, F., and Gauthier, K. (2021). Central vs. Peripheral Action. of Thyroid. Hormone in Adaptive Thermogenesis: A Burning Topic. Cells, 10. source

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  • Premisecitation

    Body composition, specifically the ratio of muscle to fat mass, exerts a considerable impact on BMR and RMR.

    “Body composition, specifically the ratio of muscle to fat mass, exerts a considerable impact on the BMR and RMR.”
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    • cites [11] McNab, B.K. (2019). What determines the basal rate of metabolism?. J. Exp. Biol., 222. source

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    Premisecitation

    According to the weight set point theory, body weight is maintained within a relatively stable range by a biological feedback system that adjusts food intake and energy expenditure.

    “According to this theory, body weight is maintained within a relatively stable range by a biological feedback system that adjusts food intake and energy expenditure [5].”
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    • cites [5] Heymsfield, 2010, Is there evidence for a set point that regulates human body weight?, F1000 Med. Rep.

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    Interpretationcitation

    Body composition, genetic predispositions, insulin sensitivity, and individual hormonal profiles collectively drive adaptive responses, creating unique weight outcomes for each person.

    “Factors such as body composition, genetic predispositions, insulin sensitivity, and individual hormonal profiles collectively drive these responses, creating unique weight outcomes for each person [6,7].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Benton, 2017, Reducing Calorie Intake May Not Help You Lose Body Weight, Perspect. Psychol. Sci. source

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    • cites [7] Greenway, 2015, Physiological adaptations to weight loss and factors favouring weight regain, Int. J. Obes. source

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

    Premisecitation

    The global age-standardized prevalence of obesity increased from 4.6% in 1980 to 14.0% in 2019.

    “Obesity rates are rising globally, with the age-standardized prevalence increasing from 4.6% in 1980 to 14.0% in 2019 [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Boutari, 2022, A 2022 update on the epidemiology of obesity and a call to action: As its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on, Metabolism source

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    Premisecitation

    A lower fiber, high-GI food like white crystalline sugar causes a rapid spike in blood glucose, leading to a quick insulin response that promotes lipogenesis and often stimulates hunger soon after.

    “In contrast, a lower fiber, high-GI food like white crystalline sugar causes a rapid spike in blood glucose, leading to a quick insulin response that promotes lipogenesis and often stimulates hunger soon after [2].”
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    • cites [2] Ludwig, 2021, The carbohydrate-insulin model: A physiological perspective on the obesity pandemic, Am. J. Clin. Nutr. source

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    Interpretationreasoning

    The set point is not absolute and likely allows for a range of variability influenced by metabolic adaptations, hormonal fluctuations, and environmental factors such as exercise, nutrition, sleep, and stress.

    “However, this set point is not absolute and likely allows for a range of variability, influenced by factors such as metabolic adaptations, hormonal fluctuations, and environmental factors, such as exercise, nutrition, sleep, and stress.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Food energy labels are allowed a margin of variability, with calorie counts fluctuating by up to 20% according to regulatory standards, and in practice discrepancies can be as high as 60%.

    “Firstly, food energy labels are allowed a margin of variability, with calorie counts fluctuating by up to 20% according to regulatory standards; however, in practice, discrepancies can be as high as 60% [3,4].”
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    • cites [3] Fabiansson, 2006, Precision in nutritional information declarations on food labels in Australia, Asia Pac. J. Clin. Nutr.

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    • cites [4] Jumpertz, 2013, Food label accuracy of common snack foods, Obesity source

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    Premisecitation

    The "calories in, calories out" model assumes that caloric expenditure and intake are accurately measurable and linearly related to weight loss.

    “The “calories in, calories out” model, also known as the dominant energy balance model, assumes that caloric expenditure and intake are accurately measurable and linearly related to weight loss [2].”
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    • cites [2] Ludwig, 2021, The carbohydrate-insulin model: A physiological perspective on the obesity pandemic, Am. J. Clin. Nutr. source

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    Premisecitation

    Reduced insulin during caloric restriction diminishes activation of anorexigenic pathways in the hypothalamus, lowering satiety and enhancing the appetite-promoting effects of NPY and AgRP neurons.

    “Reduced insulin leads to diminished activation of anorexigenic pathways in the hypothalamus, lowering satiety and enhancing the appetite-promoting effects of NPY and AgRP neurons [32].”
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    • cites [32] Freire, 2020, Appetite control: Hormones or diet strategies?, Curr. Opin. Clin. Nutr. Metab. Care source

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    Premisecitation

    Under caloric restriction, SNS activity decreases, reducing norepinephrine release and β-adrenergic receptor stimulation, especially in BAT, where UCP1 activity drops.

    “Under caloric restriction, SNS activity decreases, reducing norepinephrine release and β-adrenergic receptor stimulation, especially in BAT, where mitochondrial uncoupling protein (UCP1) activity drops.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [26] Rosenbaum, 2010, Adaptive thermogenesis in humans, Int. J. Obes. source

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    • cites [27] 2013, Adaptive thermogenesis with weight loss in humans, Obesity source

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    • cites [31] Paulo, E., Wu, D., Wang, Y., Zhang, Y., Wu, Y., Swaney, D.L., Soucheray, M., Jimenez-Morales, D., Chawla, A., and Krogan, N.J. (2018). Sympathetic inputs regulate adaptive thermogenesis in brown adipose tissue through cAMP-Salt inducible kinase axis. Sci. Rep., 8. source

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    Premisecitation

    In a study by Doucet et al., increased fasting hunger, desire to eat, and prospective food consumption were observed after both a 15-week weight-loss program and an 18-week maintenance phase, with correlations between cortisol changes and appetite measures in men (e.g., desire to eat, r = 0.67, p < 0.05) and women (e.g., desire to eat, r = 0.76, p < 0.05).

    “The results showed increased fasting hunger, desire to eat, and prospective food consumption after both phases, with correlations between cortisol changes and appetite measures in men (e.g., desire to eat, r = 0.67, p < 0.05) and women (e.g., desire to eat, r = 0.76, p < 0.05).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Doucet, 2000, Appetite after weight loss by energy restriction and a low-fat diet-exercise follow-up, Int. J. Obes. Relat. Metab. Disord. source

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    Premisecitation

    Ghrelin acts on the hypothalamic arcuate nucleus, upregulating orexigenic neurons like NPY and AgRP, which powerfully stimulate appetite.

    “Known as the “hunger hormone”, ghrelin acts on the hypothalamic arcuate nucleus, upregulating orexigenic neurons like neuropeptide Y (NPY) and agouti-related peptide (AgRP), which powerfully stimulate appetite.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Freire, 2020, Appetite control: Hormones or diet strategies?, Curr. Opin. Clin. Nutr. Metab. Care source

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    Individuals with a higher proportion of fat mass often exhibit a lower BMR, which may predispose them to weight gain under a surplus of calories.

    “In contrast, individuals with a higher proportion of fat mass often exhibit a lower BMR, which may predispose them to weight gain, especially under a surplus of calories [11].”
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    • cites [11] McNab, B.K. (2019). What determines the basal rate of metabolism?. J. Exp. Biol., 222. source

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    Premisecitation

    Caloric restriction lowers PYY release, weakening post-meal satiety and enhancing the drive to eat.

    “Caloric restriction lowers PYY release, weakening the post-meal satiety effect and enhancing the drive to eat.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Freire, 2020, Appetite control: Hormones or diet strategies?, Curr. Opin. Clin. Nutr. Metab. Care source

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    Individuals with a greater lean body mass typically have a higher baseline energy expenditure, which can be advantageous for weight management.

    “Consequently, individuals with a greater lean body mass typically have a higher baseline energy expenditure, which can be advantageous for weight management, as it provides a greater caloric buffer.”
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    • cites [11] McNab, B.K. (2019). What determines the basal rate of metabolism?. J. Exp. Biol., 222. source

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    Premisecitation

    Endomorphs' hormonal profile often features higher baseline insulin levels and a greater anabolic response, which favors fat storage.

    “Their hormonal profile often features higher baseline insulin levels and a greater anabolic response, which favors fat storage.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Ryan-Stewart, H., Faulkner, J., and Jobson, S. (2018). The influence of somatotype on anaerobic performance. PLoS ONE, 13. source

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    • cites [9] Chiu, 2022, Estimating somatotype from a single-camera 3D body scanning system, Eur. J. Sport Sci. source

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    Premisecitation

    A systematic review of 23 studies found that most studies found no significant associations between weight cycling and changes in body weight, BMI, fat mass, or lean body mass, and no substantial evidence supported a negative impact on RMR.

    “Most studies found no significant associations between weight cycling and changes in body weight, body mass index (BMI), fat mass (FM), or lean body mass (LBM). Additionally, no substantial evidence supported a negative impact on RMR.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Sanaya, 2024, The physiological effects of weight-cycling: A review of current evidence, Curr. Obes. Rep. source

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    Premisecitation

    Endomorphs have a tendency toward fat storage and efficient energy conservation, often facing challenges in weight loss due to a lower baseline metabolic rate and metabolic efficiency that favors energy storage.

    “Endomorphs, with a tendency toward fat storage and efficient energy conservation, often face challenges in weight loss due to a lower baseline metabolic rate and a metabolic efficiency that favors energy storage.”
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    • cites [8] Ryan-Stewart, H., Faulkner, J., and Jobson, S. (2018). The influence of somatotype on anaerobic performance. PLoS ONE, 13. source

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    • cites [9] Chiu, 2022, Estimating somatotype from a single-camera 3D body scanning system, Eur. J. Sport Sci. source

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    Ectomorphs are typically lean with a lower propensity for fat storage and often have a naturally higher metabolic rate and reduced efficiency in energy storage.

    “Ectomorphs, who are typically lean with a lower propensity for fat storage, often experience a naturally higher metabolic rate and reduced efficiency in energy storage.”
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    • cites [8] Ryan-Stewart, H., Faulkner, J., and Jobson, S. (2018). The influence of somatotype on anaerobic performance. PLoS ONE, 13. source

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    • cites [9] Chiu, 2022, Estimating somatotype from a single-camera 3D body scanning system, Eur. J. Sport Sci. source

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    Premisecitation

    Fasting cortisol emerged as the strongest predictor of appetite changes, with leptin also influencing fullness in men (r = 0.68, p < 0.05) during the maintenance phase.

    “Fasting cortisol emerged as the strongest predictor of appetite changes, with leptin also influencing fullness in men (r = 0.68, p < 0.05) during the maintenance phase [33].”
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    • cites [33] Doucet, 2000, Appetite after weight loss by energy restriction and a low-fat diet-exercise follow-up, Int. J. Obes. Relat. Metab. Disord. source

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    Premisecitation

    Low leptin levels reduce hypothalamic-pituitary-thyroid axis activity, further downregulating T3 levels and exacerbating metabolic slowdown.

    “Low leptin levels also reduce hypothalamic–pituitary–thyroid axis activity, further downregulating T3 levels and exacerbating metabolic slowdown [26,27].”
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    • cites [26] Rosenbaum, 2010, Adaptive thermogenesis in humans, Int. J. Obes. source

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    • cites [27] 2013, Adaptive thermogenesis with weight loss in humans, Obesity source

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    Premisecitation

    Higher leptin and cortisol levels in endomorphs may further encourage energy storage and hinder weight loss efforts.

    “Additionally, higher leptin and cortisol levels may further encourage energy storage and hinder weight loss efforts.”
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    • cites [8] Ryan-Stewart, H., Faulkner, J., and Jobson, S. (2018). The influence of somatotype on anaerobic performance. PLoS ONE, 13. source

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    • cites [9] Chiu, 2022, Estimating somatotype from a single-camera 3D body scanning system, Eur. J. Sport Sci. source

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    Premisecitation

    Ectomorphs tend toward catabolism and may struggle to gain or maintain lean mass, particularly during caloric restriction.

    “These individuals tend toward catabolism, which means they may struggle to gain or maintain lean mass, particularly during caloric restriction.”
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    • cites [8] Ryan-Stewart, H., Faulkner, J., and Jobson, S. (2018). The influence of somatotype on anaerobic performance. PLoS ONE, 13. source

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    • cites [9] Chiu, 2022, Estimating somatotype from a single-camera 3D body scanning system, Eur. J. Sport Sci. source

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    Premisecitation

    Lowered T3 reduces mitochondrial biogenesis, oxidative phosphorylation, and basal thermogenesis, impacting energy expenditure of key tissues.

    “Lowered T3 also reduces mitochondrial biogenesis, oxidative phosphorylation, and basal thermogenesis, impacting the energy expenditure of key tissues.”
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    • cites [26] Rosenbaum, 2010, Adaptive thermogenesis in humans, Int. J. Obes. source

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    • cites [27] 2013, Adaptive thermogenesis with weight loss in humans, Obesity source

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    • cites [30] Zekri, Y., Flamant, F., and Gauthier, K. (2021). Central vs. Peripheral Action. of Thyroid. Hormone in Adaptive Thermogenesis: A Burning Topic. Cells, 10. source

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    Mesomorphs generally have a higher muscle mass, which supports an elevated BMR and aids in maintenance of lean mass during caloric deficit.

    “This body type generally has a higher muscle mass, which supports an elevated BMR, aiding in the maintenance of lean mass during caloric deficit.”
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    • cites [8] Ryan-Stewart, H., Faulkner, J., and Jobson, S. (2018). The influence of somatotype on anaerobic performance. PLoS ONE, 13. source

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    • cites [9] Chiu, 2022, Estimating somatotype from a single-camera 3D body scanning system, Eur. J. Sport Sci. source

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    Premisecitation

    During caloric restriction, GLP-1 levels decrease, weakening satiety signals and reducing insulinotropic effects that aid glucose regulation.

    “During caloric restriction, GLP-1 levels decrease, weakening satiety signals and reducing the insulinotropic effects that aid in glucose regulation.”
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    • cites [32] Freire, 2020, Appetite control: Hormones or diet strategies?, Curr. Opin. Clin. Nutr. Metab. Care source

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    Premisecitation

    During caloric restriction, leptin levels decline proportionally to fat loss, signaling an energy deficit to the hypothalamus, leading to decreased sympathetic output, lowered thermogenesis, and reduced BMR.

    “Additionally, during caloric restriction, leptin levels decline proportionally to fat loss. This reduction signals an energy deficit to the hypothalamus, leading to decreased sympathetic output, lowering thermogenesis, and reducing BMR to conserve energy.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Rosenbaum, 2010, Adaptive thermogenesis in humans, Int. J. Obes. source

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    • cites [27] 2013, Adaptive thermogenesis with weight loss in humans, Obesity source

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    Overfeeding can lead to an increase in BMR and RMR for some individuals, a phenomenon known as luxurious energy expenditure, and the degree of metabolic adaptation to overfeeding varies significantly among individuals.

    “In contrast to adaptive thermogenesis following caloric restriction, overfeeding can lead to an increase in the BMR and RMR for some individuals, a phenomenon known as “luxurious energy expenditure”.”
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    • cites [37] Joosen, 2006, Energy expenditure during overfeeding, Nutr. Metab. source

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    Premisecitation

    Testosterone stimulates myofibrillar protein synthesis via mTOR activation, enhancing muscle anabolism and reducing protein breakdown, while estrogen modulates muscle sensitivity to insulin, supporting metabolic efficiency and indirectly preserving muscle tissue.

    “Testosterone stimulates myofibrillar protein synthesis (MPS) via mechanistic target of rapamycin (mTOR) activation, enhancing muscle anabolism and reducing protein breakdown, while estrogen modulates muscle sensitivity to insulin, supporting metabolic efficiency and indirectly preserving muscle tissue [23].”
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    • cites [23] Theodorakis, 2024, Testosterone therapy for functional hypogonadism in middle-aged and elderly males: Current evidence and future perspectives, Hormones source

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    Premisecitation

    Caloric restriction triggers cortisol rise, which promotes proteolysis in skeletal muscle by activating proteolytic enzymes including the ubiquitin-proteasome system and lysosomal pathways.

    “Cortisol rises in response to caloric restriction, promoting proteolysis in skeletal muscle. Cortisol activates proteolytic enzymes, including the ubiquitin–proteasome system and lysosomal pathways, to supply amino acids for gluconeogenesis, ensuring a steady glucose supply for glucose-dependent tissues [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Knezevic, E., Nenic, K., Milanovic, V., and Knezevic, N.N. (2023). The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders. Cells, 12. source

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    Premisecitation

    UCP1 activation is driven by sympathetic stimulation through β-adrenergic receptors, and genetic variations in these receptors influence BAT responsiveness to norepinephrine.

    “UCP1 activation is driven by sympathetic stimulation through β-adrenergic receptors, and genetic variations in these receptors, especially adrenergic beta-3 receptors, influence BAT responsiveness to norepinephrine.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Liu, X., Zhang, Z., Song, Y., Xie, H., and Dong, M. (2023). An update on brown adipose tissue and obesity intervention: Function, regulation and therapeutic implications. Front. Endocrinol., 13. source

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    Premisecitation

    Overfeeding stimulates peripheral conversion of T4 to T3 via type II iodothyronine deiodinase, and elevated T3 boosts metabolic rate by increasing mitochondrial biogenesis and oxidative phosphorylation, enhancing thermogenesis.

    “Overfeeding stimulates a peripheral conversion of T4 to T3 via the enzyme type II iodothyronine deiodinase. Elevated T3 levels boost metabolic rate by increasing mitochondrial biogenesis and oxidative phosphorylation, enhancing thermogenesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Basolo, 2019, Effects of Short-Term Fasting and Different Overfeeding Diets on Thyroid Hormones in Healthy Humans, Thyroid source

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    Satellite cells are crucial for muscle hypertrophy, as they fuse to existing muscle fibers, increasing muscle mass.

    “Satellite cells, which are muscle stem cells, are crucial for muscle hypertrophy, as they fuse to existing muscle fibers, increasing muscle mass.”
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    • cites [60] Tierney, 2016, Satellite Cell Heterogeneity in Skeletal Muscle Homeostasis, Trends Cell Biol. source

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    People with more active BAT can expend excess calories more effectively, reducing fat storage.

    “People with more active BAT can expend excess calories more effectively, thus reducing fat storage [50].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Liu, X., Zhang, Z., Song, Y., Xie, H., and Dong, M. (2023). An update on brown adipose tissue and obesity intervention: Function, regulation and therapeutic implications. Front. Endocrinol., 13. source

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    Premisecitation

    In obesity with chronic hyperleptinemia, leptin resistance develops, which prevents stimulation of lipolysis and suppression of appetite and leads to insulin resistance.

    “However, in obesity with chronic hyperleptinemia, there is a development of leptin resistance, which prevents the stimulation of lipolysis and the suppression of appetite and leads to insulin resistance [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Muoio, 2002, Peripheral metabolic actions of leptin, Best. Pract. Res. Clin. Endocrinol. Metab. source

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    Premisecitation

    The SNS increases in response to caloric surplus, with norepinephrine activating β-adrenergic receptors, particularly in BAT, stimulating UCP1 and generating heat through uncoupled respiration.

    “The SNS increases in response to caloric surplus, with norepinephrine activating β-adrenergic receptors, particularly in BAT. This stimulates UCP1 in BAT mitochondria, generating heat through uncoupled respiration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Thorp, 2015, Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome, J. Diabetes Res. source

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    Premisecitation

    These hormonal changes promoting appetite and weight regain persisted one year following weight loss, with leptin (p < 0.001) and ghrelin (p < 0.001) remaining significantly altered.

    “These hormonal changes, which promote appetite and weight regain, persisted one-year following weight loss, with levels of leptin (p < 0.001) and ghrelin (p < 0.001) remaining significantly altered, suggesting a physiological basis for the high rate of weight regain [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Sumithran, 2011, Long-term persistence of hormonal adaptations to weight loss, N. Engl. J. Med. source

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    Premisecitation

    Fiber-rich diets support a more favorable microbiota that increases satiety and may limit fat gain during overfeeding.

    “Conversely, fiber-rich diets support a more favorable microbiota that increases satiety and may limit fat gain during overfeeding.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Cheng, Z., Zhang, L., Yang, L., and Chu, H. (2022). The critical role of gut microbiota in obesity. Front. Endocrinol., 13. source

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    Premisecitation

    Hormone-sensitive lipase activity increases in adipose tissue under caloric restriction as insulin levels decline, and glucagon and catecholamines stimulate HSL through β-adrenergic receptors, promoting lipolysis and releasing free fatty acids and glycerol.

    “Hormone-sensitive lipase (HSL) activity increases in adipose tissue under caloric restriction as insulin levels decline. Glucagon and catecholamines stimulate HSL through β-adrenergic receptors, promoting lipolysis and releasing free fatty acids (FFAs) and glycerol into circulation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Althaher, 2022, An Overview of Hormone-Sensitive Lipase (HSL), Sci. World J. source

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    Premisecitation

    Leptin rises in proportion to body fat, increases energy expenditure by stimulating sympathetic outflow and enhancing UCP1 expression in BAT, augments fatty acid oxidation, and reduces lipogenic pathways in peripheral tissues.

    “Rising in proportion to body fat, leptin increases energy expenditure by stimulating sympathetic outflow and enhancing UCP1 expression in BAT. Leptin also augments fatty acid oxidation and reduces lipogenic (fat storage) pathways in peripheral tissues, limiting fat accumulation during overfeeding.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Muoio, 2002, Peripheral metabolic actions of leptin, Best. Pract. Res. Clin. Endocrinol. Metab. source

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    Premisecitation

    Poor sleep quality is linked to increased ghrelin and decreased leptin, enhancing hunger and potentially leading to higher caloric intake during overfeeding.

    “Poor sleep quality is linked to increased ghrelin levels and decreased leptin levels, enhancing hunger and potentially leading to higher caloric intake during overfeeding [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Meth, 2023, Effects of acute sleep loss on leptin, ghrelin, and adiponectin in adults with healthy weight and obesity: A laboratory study, Obesity source

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    Premisecitation

    In the study by Sumithran et al., significant weight loss (mean 13.5 ± 0.5 kg) led to reductions in leptin, PYY, CCK, and insulin levels (p < 0.001), while ghrelin and gastric inhibitory polypeptide levels increased (p < 0.001).

    “Significant weight loss (mean 13.5 ± 0.5 kg) led to reductions in leptin, PYY, cholecystokinin (CCK), and insulin levels (p < 0.001), while ghrelin and gastric inhibitory polypeptide levels increased (p < 0.001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Sumithran, 2011, Long-term persistence of hormonal adaptations to weight loss, N. Engl. J. Med. source

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    Premisecitation

    AKT1 rs1130214 polymorphism affects the AKT pathway, influencing MPS rates.

    “Furthermore, the AKT1 rs1130214 polymorphism affects the AKT pathway, a critical component of the mTOR signaling cascade, influencing MPS rates [59].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Jaiswal, 2019, The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasis, Mol. Metab. source

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    Premisecitation

    Growth hormone levels may increase with caloric restriction, stimulating lipolysis and reducing muscle protein breakdown by inhibiting the effects of cortisol.

    “Growth hormone (GH) levels may increase with caloric restriction, stimulating lipolysis and reducing muscle protein breakdown by inhibiting the effects of cortisol.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Theodorakis, N., Feretzakis, G., Kreouzi, M., Anagnostou, D., Hitas, C., Verykios, V.S., and Nikolaou, M. (2024). Growth Hormone Therapy in Chronic Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J. Clin. Endocrinol. Metab., dgae814. source

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    Premisecitation

    Individuals with GHR polymorphisms that enhance receptor activity experience more pronounced muscle growth in response to GH, as IGF-1 stimulates MPS and reduces protein degradation.

    “Individuals with GHR polymorphisms that enhance receptor activity experience more pronounced muscle growth in response to GH, as IGF-1 stimulates MPS and reduces protein degradation [57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Dehkhoda, F., Lee, C.M.M., Medina, J., and Brooks, A.J. (2018). The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects. Front. Endocrinol., 9. source

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    Premisecitation

    Chronic stress elevates cortisol, which can impair insulin sensitivity and promote visceral fat storage.

    “Additionally, chronic stress elevates cortisol, which can impair insulin sensitivity and promote visceral fat storage [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Hewagalamulage, 2016, Stress, cortisol, and obesity: A role for cortisol responsiveness in identifying individuals prone to obesity, Domest. Anim. Endocrinol. source

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  • May combine two claims.

    Premisecitation

    Exercise can reduce methylation of lipolytic genes and increase fat oxidation capacity.

    “Epigenetic influences are also shaped by factors like exercise, which can reduce methylation of lipolytic genes and increase fat oxidation capacity [74].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Kandror, 2017, Mammalian target of rapamycin complex 1 and FoxO1 in the transcriptional control of lipolysis and de novo lipogenesis, Curr. Opin. Endocrinol. Diabetes Obes. source

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    Premisecitation

    Individuals with heightened β-adrenergic sensitivity experience faster lipolysis, mobilizing fat stores more efficiently during restriction, whereas those with reduced sensitivity may struggle to achieve the same level of fat oxidation.

    “Individuals with heightened β-adrenergic sensitivity experience faster lipolysis, mobilizing fat stores more efficiently during restriction, whereas those with reduced receptor sensitivity may struggle to achieve the same level of fat oxidation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Izaola, 2023, Role of beta-2 adrenergic receptor polymorphism (rs1042714) on body weight and glucose metabolism response to a meal-replacement hypocaloric diet, Nutrition source

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    • cites [71] Masuo, 2005, Beta2- and beta3-adrenergic receptor polymorphisms are related to the onset of weight gain and blood pressure elevation over 5 years, Circulation source

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    Premisecitation

    Resistance training enhances anabolic signaling and increases muscle hypertrophy when combined with overfeeding.

    “Resistance training enhances anabolic signaling and increases muscle hypertrophy when combined with overfeeding.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Masschelein, 2022, Resistance exercise enhances long-term mTORC1 sensitivity to leucine, Mol. Metab. source

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    Premisecitation

    High-volume resistance training induces greater activation of the PI3K-AKT-mTOR pathway, increasing MPS rates and amplifying caloric surplus effects.

    “High-volume resistance training induces a greater activation of the PI3K–AKT–mTOR pathway, increasing MPS rates and amplifying caloric surplus effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Masschelein, 2022, Resistance exercise enhances long-term mTORC1 sensitivity to leucine, Mol. Metab. source

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    Premisecitation

    Differences in AR density and sensitivity modulate individual muscle gain capacity, with higher AR density responding more robustly to testosterone.

    “Differences in AR density and sensitivity modulate individual muscle gain capacity, with those exhibiting higher AR density responding more robustly to testosterone [23].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Theodorakis, 2024, Testosterone therapy for functional hypogonadism in middle-aged and elderly males: Current evidence and future perspectives, Hormones source

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  • May combine two claims.

    Premisecitation

    In human skeletal muscle cells, leucine independently and transiently stimulated mTOR signaling without affecting amino acid transporter gene expression.

    “The results showed that leucine independently and transiently stimulated mTOR signaling without affecting amino acid transporter gene expression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Gran, P., and Cameron-Smith, D. (2011). The actions of exogenous leucine on mTOR signalling and amino acid transporters in human myotubes. BMC Physiol., 11. source

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    Premisecitation

    Insulin increased mTOR signaling and modified gene expression of amino acid transporters in human myotubes.

    “However, insulin also increased mTOR signaling and modified the gene expression of amino acid transporters.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Gran, P., and Cameron-Smith, D. (2011). The actions of exogenous leucine on mTOR signalling and amino acid transporters in human myotubes. BMC Physiol., 11. source

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    Premisecitation

    Ketone body production is crucial for energy provision during caloric restriction, reducing glucose demand and muscle breakdown.

    “Ketone body production (ketogenesis) is crucial for energy provision during caloric restriction, as it reduces glucose demand and muscle breakdown.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [75] Grabacka, M., Pierzchalska, M., Dean, M., and Reiss, K. (2016). Regulation of Ketone Body Metabolism and the Role of PPARα. Int. J. Mol. Sci., 17. source

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    • cites [76] Ruscica, M., Busnelli, M., Runfola, E., Corsini, A., and Sirtori, C.R. (2019). Impact of PPAR-Alpha Polymorphisms—The Case of Metabolic Disorders and Atherosclerosis. Int. J. Mol. Sci., 20. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Muscle growth is heavily dependent on MPS, which is regulated by mTOR signaling and ribosomal biogenesis.

    “Muscle growth is heavily dependent on MPS, which is regulated by mTOR signaling and ribosomal biogenesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Leucine enhanced expression of hVps34, which may regulate amino acid transport and mTOR activation in muscle tissue.

    “Notably, leucine enhanced the expression of the nutrient-sensing protein hVps34, which may regulate amino acid transport and mTOR activation in muscle tissue [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Gran, P., and Cameron-Smith, D. (2011). The actions of exogenous leucine on mTOR signalling and amino acid transporters in human myotubes. BMC Physiol., 11. source

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  • May combine two claims.

    Premisereasoning

    This adaptation spares glucose, facilitating sustained fat loss without loss of lean mass.

    “This adaptation spares glucose, facilitating sustained fat loss without the loss of lean mass.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Grabacka, M., Pierzchalska, M., Dean, M., and Reiss, K. (2016). Regulation of Ketone Body Metabolism and the Role of PPARα. Int. J. Mol. Sci., 17. source

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    • cites [76] Ruscica, M., Busnelli, M., Runfola, E., Corsini, A., and Sirtori, C.R. (2019). Impact of PPAR-Alpha Polymorphisms—The Case of Metabolic Disorders and Atherosclerosis. Int. J. Mol. Sci., 20. source

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  • May combine two claims.

    Premisereasoning

    Individuals with high PPAR-α expression or activity adapt more readily to fat oxidation, entering ketosis more efficiently.

    “Individuals with high PPAR-α expression or activity adapt more readily to fat oxidation, entering ketosis more efficiently.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [75] Grabacka, M., Pierzchalska, M., Dean, M., and Reiss, K. (2016). Regulation of Ketone Body Metabolism and the Role of PPARα. Int. J. Mol. Sci., 17. source

      Not checked in the free run.

    • cites [76] Ruscica, M., Busnelli, M., Runfola, E., Corsini, A., and Sirtori, C.R. (2019). Impact of PPAR-Alpha Polymorphisms—The Case of Metabolic Disorders and Atherosclerosis. Int. J. Mol. Sci., 20. source

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  • May combine two claims.

    Premisecitation

    HIIT increases mitochondrial density and function within muscle cells, enhancing capacity to use free fatty acids, especially in individuals with previously low aerobic capacity.

    “HIIT has been shown to increase mitochondrial density and function within muscle cells, enhancing the muscles’ capacity to use free fatty acids for energy, especially in individuals with previously low aerobic capacity.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] Sun, 2020, Effects of high-intensity interval training on adipose tissue lipolysis, inflammation, and metabolomics in aged rats, Pflugers Arch. source

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    • cites [79] Torma, 2019, High intensity interval training and molecular adaptive response of skeletal muscle, Sports Med. Health Sci. source

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    Premisecitation

    In controlled settings, high-carbohydrate and high-protein diets can improve satiety and metabolic balance, contributing to weight maintenance rather than fat gain.

    “In controlled settings, high-carbohydrate and high-protein diets can improve satiety and metabolic balance, contributing to weight maintenance rather than fat gain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Hall, 2022, The energy balance model of obesity: Beyond calories in, calories out, Am. J. Clin. Nutr. source

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    Premisecitation

    Testosterone and estrogen play essential roles in muscle preservation, with testosterone promoting MPS via mTOR and estrogen supporting metabolic efficiency and glucose utilization.

    “Testosterone and estrogen play essential roles in muscle preservation, with testosterone promoting MPS via mTOR activation and estrogen supporting metabolic efficiency and glucose utilization.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Theodorakis, 2024, Testosterone therapy for functional hypogonadism in middle-aged and elderly males: Current evidence and future perspectives, Hormones source

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    • cites [86] Critchlow, 2023, The role of estrogen in female skeletal muscle aging: A systematic review, Maturitas source

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  • May combine two claims.

    Premisecitation

    Increased AMPK activity enhances mitochondrial biogenesis, supporting sustained fat oxidation and muscle preservation under caloric deficit.

    “Increased AMPK activity enhances mitochondrial biogenesis, supporting sustained fat oxidation and muscle preservation under caloric deficit [83,84].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [83] Wu, L., Zhang, L., Li, B., Jiang, H., Duan, Y., Xie, Z., Shuai, L., Li, J., and Li, J. (2018). AMP-Activated Protein Kinase (AMPK) Regulates Energy Metabolism through Modulating Thermogenesis in Adipose Tissue. Front. Physiol., 9. source

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    • cites [84] Kopietz, 2023, Metabolic control by AMPK in white adipose tissue, Trends Endocrinol. Metab. source

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  • May combine two claims.

    Premisecitation

    HIIT significantly promotes lipolysis, making it effective for reducing body fat and improving metabolic health.

    “High-intensity interval training (HIIT) significantly promotes lipolysis, making it an effective strategy for reducing body fat and improving metabolic health.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] Sun, 2020, Effects of high-intensity interval training on adipose tissue lipolysis, inflammation, and metabolomics in aged rats, Pflugers Arch. source

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    • cites [79] Torma, 2019, High intensity interval training and molecular adaptive response of skeletal muscle, Sports Med. Health Sci. source

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  • May combine two claims.

    Premisecitation

    AMPK is activated under low energy states, enhancing fat oxidation and reducing reliance on muscle protein for energy.

    “Adenosine monophosphate-activated protein kinase (AMPK) is activated under low energy states, enhancing fat oxidation and reducing reliance on muscle protein for energy.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [83] Wu, L., Zhang, L., Li, B., Jiang, H., Duan, Y., Xie, Z., Shuai, L., Li, J., and Li, J. (2018). AMP-Activated Protein Kinase (AMPK) Regulates Energy Metabolism through Modulating Thermogenesis in Adipose Tissue. Front. Physiol., 9. source

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    • cites [84] Kopietz, 2023, Metabolic control by AMPK in white adipose tissue, Trends Endocrinol. Metab. source

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  • May combine two claims.

    Premisecitation

    Myoglobin-rich type I fibers facilitate oxygen delivery, optimizing oxidative metabolism and reducing protein breakdown.

    “Additionally, myoglobin-rich type I fibers facilitate oxygen delivery, optimizing oxidative metabolism and reducing protein breakdown.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Guilherme, J.P.L.F., Semenova, E.A., Kikuchi, N., Homma, H., Kozuma, A., Saito, M., Zempo, H., Matsumoto, S., Kobatake, N., and Nakazato, K. (2024). Identification of Genomic Predictors of Muscle Fiber Size. Cells, 13. source

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  • May combine two claims.

    Premisecitation

    HIIT is associated with increased levels of adiponectin, further supporting its role in enhancing fat metabolism.

    “Additionally, HIIT has been associated with increased levels of adiponectin, an adipokine that regulates glucose levels and fatty acid breakdown, further supporting the role of HIIT in enhancing fat metabolism.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] Sun, 2020, Effects of high-intensity interval training on adipose tissue lipolysis, inflammation, and metabolomics in aged rats, Pflugers Arch. source

      Not checked in the free run.

    • cites [79] Torma, 2019, High intensity interval training and molecular adaptive response of skeletal muscle, Sports Med. Health Sci. source

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    Premisecitation

    Adiponectin enhances fatty acid oxidation and improves insulin sensitivity.

    “Adiponectin, secreted by adipocytes, enhances fatty acid oxidation and improves insulin sensitivity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Khabour, 2018, The Relationship of adiponectin level and ADIPOQ gene variants with BMI among young adult women, Dermato-Endocrinology source

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    Premisecitation

    Genetic variations in AMPK subunit genes and epigenetic modifications affecting AMPK expression can influence the extent of this energy shift.

    “Genetic variations in AMPK subunit genes (PRKAA1, PRKAA2) and epigenetic modifications affecting AMPK expression can influence the extent of this energy shift.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [83] Wu, L., Zhang, L., Li, B., Jiang, H., Duan, Y., Xie, Z., Shuai, L., Li, J., and Li, J. (2018). AMP-Activated Protein Kinase (AMPK) Regulates Energy Metabolism through Modulating Thermogenesis in Adipose Tissue. Front. Physiol., 9. source

      Not checked in the free run.

    • cites [84] Kopietz, 2023, Metabolic control by AMPK in white adipose tissue, Trends Endocrinol. Metab. source

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  • May combine two claims.

    Premisecitation

    Chronic stress elevates cortisol, which promotes visceral fat storage and impairs lipolysis by increasing insulin resistance.

    “Chronic stress elevates cortisol, which promotes visceral fat storage and impairs lipolysis by increasing insulin resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Hewagalamulage, 2016, Stress, cortisol, and obesity: A role for cortisol responsiveness in identifying individuals prone to obesity, Domest. Anim. Endocrinol. source

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  • May combine two claims.

    Premisecitation

    Individuals with high AMPK activation efficiently switch to fat as a fuel source, preserving muscle mass during restriction.

    “Individuals with high AMPK activation efficiently switch to fat as a fuel source, preserving muscle mass during restriction.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [83] Wu, L., Zhang, L., Li, B., Jiang, H., Duan, Y., Xie, Z., Shuai, L., Li, J., and Li, J. (2018). AMP-Activated Protein Kinase (AMPK) Regulates Energy Metabolism through Modulating Thermogenesis in Adipose Tissue. Front. Physiol., 9. source

      Not checked in the free run.

    • cites [84] Kopietz, 2023, Metabolic control by AMPK in white adipose tissue, Trends Endocrinol. Metab. source

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  • May combine two claims.

    Premisecitation

    The proportion of oxidative type I versus glycolytic type II muscle fibers influences muscle preservation, as type I fibers are more resistant to proteolysis and rely on fatty acid oxidation.

    “The proportion of oxidative (type I) versus glycolytic (type II) muscle fibers influences muscle preservation, as type I fibers are more resistant to proteolysis and rely heavily on fatty acid oxidation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Guilherme, J.P.L.F., Semenova, E.A., Kikuchi, N., Homma, H., Kozuma, A., Saito, M., Zempo, H., Matsumoto, S., Kobatake, N., and Nakazato, K. (2024). Identification of Genomic Predictors of Muscle Fiber Size. Cells, 13. source

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  • May combine two claims.

    Premisecitation

    In a similar study, protein intakes of 1.6 and 2.4 g/kg were more effective in preserving lean body mass compared to 0.8 g/kg, with no substantial additional benefit at 2.4 over 1.6.

    “A similar study evaluated protein intakes of 0.8 g/kg, 1.6 g/kg, and 2.4 g/kg per day, revealing that both higher intake levels (1.6 and 2.4 g/kg) were more effective in preserving lean body mass compared to the lower 0.8 g/kg intake. Interestingly, no substantial additional benefit was observed at 2.4 g/kg over 1.6 g/kg [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Pasiakos, 2013, Effects of high-protein diets on fat-free mass and muscle protein synthesis following weight loss: A randomized controlled trial, FASEB J. source

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  • May combine two claims.

    Premisecitation

    Women with higher estrogen levels benefit from estrogen's mitochondrial protective effects, enhancing oxidative capacity and reducing proteolysis.

    “Women with higher estrogen levels benefit from estrogen’s mitochondrial protective effects, which enhance oxidative capacity and reduce proteolysis, as it reduces reliance on amino acids for gluconeogenesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Critchlow, 2023, The role of estrogen in female skeletal muscle aging: A systematic review, Maturitas source

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  • May combine two claims.

    Premisecitation

    Chronic stress elevates cortisol, which has catabolic effects on muscle tissue.

    “Stress management is equally critical, as chronic stress elevates cortisol, a glucocorticoid hormone known to have catabolic effects on muscle tissue.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Katsuhara, 2022, Impact of Cortisol on Reduction in Muscle Strength and Mass: A Mendelian Randomization Study, J. Clin. Endocrinol. Metab. source

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  • May combine two claims.

    Premisecitation

    Adequate sleep supports recovery, optimizes hormone balance particularly GH, and enhances mTOR signaling and MPS.

    “Adequate sleep supports recovery, optimizes hormone balance—particularly GH, which peaks during slow-wave sleep and is essential for muscle repair and regeneration—and enhances mTOR signaling and therefore MPS.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [86] Critchlow, 2023, The role of estrogen in female skeletal muscle aging: A systematic review, Maturitas source

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    • cites [91] Morrison, 2022, Sleep, circadian biology and skeletal muscle interactions: Implications for metabolic health, Sleep Med. Rev. source

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  • May combine two claims.

    Premisecitation

    In the NOW trial, at 12 months only the GLB + NGx group achieved a significant reduction in total fat intake and greater adherence to fat and saturated fat guidelines.

    “At 12 months, only the GLB + NGx group achieved a significant reduction in total fat intake from 36.0% ± 4.8% kcal to 30.2% ± 8.7% kcal (p = 0.02) and greater adherence to fat and saturated fat guidelines (p < 0.05).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Horne, 2020, Enhanced long-term dietary change and adherence in a nutrigenomics-guided lifestyle intervention compared to a population-based (GLB/DPP) lifestyle intervention for weight management: Results from the NOW randomised controlled trial, BMJ Nutr. Prev. Health source

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  • May combine two claims.

    Interpretationcitation

    PREDICT1 underscores significant variability in metabolic responses between individuals, even among twins, due to modifiable factors, supporting the potential for personalized nutrition strategies in reducing cardiometabolic risk.

    “This study underscores significant variability in metabolic responses between individuals, even among twins, due to modifiable factors, which supports the potential for personalized nutrition strategies in reducing cardiometabolic risk [94].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Berry, 2020, Human postprandial responses to food and potential for precision nutrition, Nat. Med. source

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    Premisecitation

    In PREDICT1, genetic factors explained 9.5% of glycemic response variance, with less influence on triglyceride and C-peptide responses.

    “Genetic factors showed a modest impact, explaining 9.5% of glycemic response variance (p < 0.05), with less influence on triglyceride (0.8%) and C-peptide responses (0.2%) [94].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Berry, 2020, Human postprandial responses to food and potential for precision nutrition, Nat. Med. source

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  • May combine two claims.

    Premisecitation

    Insufficient sleep elevates cortisol, promoting muscle breakdown through increased proteolysis.

    “Additionally, insufficient sleep elevates cortisol levels, further promoting muscle breakdown through increased proteolysis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Morrison, 2022, Sleep, circadian biology and skeletal muscle interactions: Implications for metabolic health, Sleep Med. Rev. source

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  • May combine two claims.

    Premisecitation

    IC-guided energy delivery did not significantly affect mechanical ventilation duration, ICU stay, hospital stay, or long-term mortality.

    “However, it did not significantly affect mechanical ventilation duration, ICU stay, hospital stay, or long-term mortality, suggesting IC’s utility in improving short-term outcomes [95].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Duan, 2021, Energy delivery guided by indirect calorimetry in critically ill patients: A systematic review and meta-analysis, Crit. Care source

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  • May combine two claims.

    Premisecitation

    In the DIETFITS trial, no significant diet-genotype interaction or diet-insulin interaction was observed.

    “Additionally, no significant diet–genotype interaction (p = 0.20) or diet–insulin interaction (p = 0.47) was observed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Gardner, 2018, Effect of Low-Fat vs. Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association with Genotype Pattern or Insulin Secretion: The DIETFITS Randomized Clinical Trial, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In PREDICT1, machine learning models predicted triglyceride and glycemic responses and were validated in the US cohort with similar accuracy.

    “The ML models developed from these data predicted triglyceride (r = 0.47, p < 0.001) and glycemic (r = 0.77, p < 0.001) responses, validated in the US cohort with similar accuracy (r = 0.42 for triglyceride, r = 0.75 for glucose).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Berry, 2020, Human postprandial responses to food and potential for precision nutrition, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the DIETFITS trial, secondary outcomes favored the healthy low-fat diet for LDL and the healthy low-carbohydrate diet for HDL and triglycerides.

    “Secondary outcomes favored HLF for low-density lipoprotein (−5.74 mg/dL; 95% CI, −9.38 to −2.09) and HLC for high-density lipoprotein cholesterol (2.24 mg/dL; 95% CI, −3.33 to −1.15) and triglycerides (−18.25 mg/dL; 95% CI, −28.84 to −7.65) [92].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Gardner, 2018, Effect of Low-Fat vs. Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association with Genotype Pattern or Insulin Secretion: The DIETFITS Randomized Clinical Trial, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Disrupted sleep impairs GH secretion, limiting muscle repair and activating a catabolic state.

    “Disrupted sleep, on the other hand, impairs GH secretion, limiting muscle repair and activating a catabolic state that makes muscle tissue more prone to breakdown [86].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Critchlow, 2023, The role of estrogen in female skeletal muscle aging: A systematic review, Maturitas source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leucine directly activates mTORC1 at the cellular level, enhancing translation and assembly of muscle proteins.

    “Leucine’s role is crucial, as it directly activates mTORC1 at the cellular level, enhancing the translation and assembly of muscle proteins, leading to more effective muscle maintenance or growth even during periods of reduced calorie intake [65].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Masschelein, 2022, Resistance exercise enhances long-term mTORC1 sensitivity to leucine, Mol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resistance exercise preserves muscle mass during weight loss by activating the mTOR pathway and MPS, counteracting muscle proteolysis.

    “Resistance exercise plays a fundamental role in preserving muscle mass during weight loss by activating the mTOR pathway and subsequently MPS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Mazo, 2021, The effects of acute aerobic and resistance exercise on mTOR signaling and autophagy markers in untrained human skeletal muscle, Eur. J. Appl. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cortisol contributes to age-related sarcopenia by promoting protein degradation and inhibiting muscle synthesis, with elevated glucose possibly accelerating these effects.

    “The findings suggest that cortisol contributes to age-related sarcopenia by promoting protein degradation and inhibiting muscle synthesis, with elevated glucose levels possibly accelerating these effects [90].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Katsuhara, 2022, Impact of Cortisol on Reduction in Muscle Strength and Mass: A Mendelian Randomization Study, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Variations in the AR gene influence testosterone's efficacy in maintaining lean mass, with certain polymorphisms enhancing muscle preservation during caloric restriction.

    “Furthermore, variations in the AR gene influence testosterone’s efficacy in maintaining lean mass, with certain polymorphisms enhancing muscle preservation during caloric restriction [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Theodorakis, 2024, Testosterone therapy for functional hypogonadism in middle-aged and elderly males: Current evidence and future perspectives, Hormones source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The NOW trial suggests that personalized, genetic-based advice enhances dietary change beyond traditional guidelines, supporting nutrigenomics as an effective tool for sustained weight management.

    “The study incorporated the theory of planned behavior to control confounders, suggesting that personalized, genetic-based advice enhances dietary change beyond traditional guidelines, supporting nutrigenomics as an effective tool for sustained weight management [93].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Horne, 2020, Enhanced long-term dietary change and adherence in a nutrigenomics-guided lifestyle intervention compared to a population-based (GLB/DPP) lifestyle intervention for weight management: Results from the NOW randomised controlled trial, BMJ Nutr. Prev. Health source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a meta-analysis, IC-guided nutrition provided higher mean daily energy intake and improved alignment with resting energy expenditure targets compared with predictive equations.

    “IC-guided nutrition provided higher mean daily energy intake (622 kcal/day, p < 0.00001) and improved alignment with resting energy expenditure targets (89–106% in the IC group versus 56–79% in the control).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Duan, 2021, Energy delivery guided by indirect calorimetry in critically ill patients: A systematic review and meta-analysis, Crit. Care source

      Not checked in the free run.

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

    Interpretationreasoning

    Precision medicine uses these insights to identify personalized strategies, potentially overcoming adaptive mechanisms like metabolic slowdown or resistance to fat loss.

    “Precision medicine uses these insights to identify personalized strategies, potentially overcoming adaptive mechanisms like metabolic slowdown or resistance to fat loss.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Wearable devices provide real-time physiological data, while advanced biomarkers offer deeper insights into metabolic states.

    “Wearable devices, such as continuous glucose monitors (CGMs) and smartwatches, provide real-time physiological data, while advanced biomarkers, including metabolomic and proteomic profiles, offer deeper insights into metabolic states.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [96] Kirk, D., Catal, C., and Tekinerdogan, B. (2021). Precision nutrition: A systematic literature review. Comput. Biol. Med., 133. source

      Not checked in the free run.

    • cites [97] Theodorakis, N., Feretzakis, G., Tzelves, L., Paxinou, E., Hitas, C., Vamvakou, G., Verykios, V.S., and Nikolaou, M. (2024). Integrating Machine Learning with Multi-Omics Technologies in Geroscience: Towards Personalized Medicine. J. Pers. Med., 14. source

      Not checked in the free run.

    • cites [98] Miyazawa, 2022, Artificial intelligence in food science and nutrition: A narrative review, Nutr. Rev. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Many studies fail to adequately control for confounding factors such as sleep quality, stress levels, or dietary composition.

    “Many studies fail to adequately control for confounding factors, such as sleep quality, stress levels, or dietary composition, which significantly influence metabolic responses and hormonal adaptations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    These findings underscore the role of strength training in reducing lipid accumulation, enhancing fatty acid oxidation, and regulating key molecular pathways that mitigate insulin resistance.

    “These findings underscore the role of strength training in not only reducing lipid accumulation and enhancing fatty acid oxidation but also in regulating key molecular pathways that mitigate insulin resistance [104].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Zheng, L., Rao, Z., Wu, J., Ma, X., Jiang, Z., and Xiao, W. (2024). Resistance Exercise Improves Glycolipid Metabolism and Mitochondrial Biogenesis in Skeletal Muscle of T2DM Mice via miR-30d-5p/SIRT1/PGC-1α Axis. Int. J. Mol. Sci., 25. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This increase in muscle mass counteracts metabolic adaptations, such as the reduction in energy expenditure often observed during caloric restriction, thereby enhancing the sustainability of weight loss efforts.

    “This increase in muscle mass also counteracts metabolic adaptations, such as the reduction in energy expenditure often observed during caloric restriction, thereby enhancing the sustainability of weight loss efforts.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Zheng, L., Rao, Z., Wu, J., Ma, X., Jiang, Z., and Xiao, W. (2024). Resistance Exercise Improves Glycolipid Metabolism and Mitochondrial Biogenesis in Skeletal Muscle of T2DM Mice via miR-30d-5p/SIRT1/PGC-1α Axis. Int. J. Mol. Sci., 25. source

      Not checked in the free run.

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

    Study design and conductnone given

    Environmental and epigenetic influences are underexplored in the context of long-term weight management outcomes.

    “While the role of genetic predispositions is often addressed, environmental and epigenetic influences, such as dietary patterns, socioeconomic status, and early-life exposures, are underexplored in the context of long-term weight management outcomes.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    These data refine dietary and exercise strategies, targeting specific outcomes, such as fat loss or muscle gain.

    “These data refine dietary and exercise strategies, targeting specific outcomes, such as fat loss or muscle gain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Duan, 2021, Energy delivery guided by indirect calorimetry in critically ill patients: A systematic review and meta-analysis, Crit. Care source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    AI-aided platforms optimize caloric intake and macronutrient distribution based on the user's metabolic and hormonal profiles, addressing adaptive responses such as metabolic slowdown during caloric restriction.

    “AI-aided platforms optimize caloric intake and macronutrient distribution based on the user’s metabolic and hormonal profiles, addressing individual adaptive responses such as metabolic slowdown during caloric restriction.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [96] Kirk, D., Catal, C., and Tekinerdogan, B. (2021). Precision nutrition: A systematic literature review. Comput. Biol. Med., 133. source

      Not checked in the free run.

    • cites [97] Theodorakis, N., Feretzakis, G., Tzelves, L., Paxinou, E., Hitas, C., Vamvakou, G., Verykios, V.S., and Nikolaou, M. (2024). Integrating Machine Learning with Multi-Omics Technologies in Geroscience: Towards Personalized Medicine. J. Pers. Med., 14. source

      Not checked in the free run.

    • cites [98] Miyazawa, 2022, Artificial intelligence in food science and nutrition: A narrative review, Nutr. Rev. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    Targeting pre-obesity-defined as an intermediate stage with a BMI nearing 25-29.9 kg/m2-offers a critical window for intervention.

    “Emerging evidence suggests that targeting pre-obesity—defined as an intermediate stage with a BMI nearing 25–29.9 kg/m2—offers a critical window for intervention.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Dhanjani, S., Allen, H., Varman, B., Callender, C., Dave, J.M., and Thompson, D. (2024). Community-Based Participatory Obesity Prevention Interventions in Rural Communities: A Scoping Review. Nutrients, 16. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    By preserving and increasing muscle mass, strength training supports metabolic health, improves physical performance, and reduces the risk of falls and frailty.

    “By preserving and increasing muscle mass, strength training not only supports metabolic health but also improves physical performance and reduces the risk of falls and frailty.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Theodorakis, N., Nikolaou, M., Hitas, C., Anagnostou, D., Kreouzi, M., Kalantzi, S., Spyridaki, A., Triantafylli, G., Metheniti, P., and Papaconstantinou, I. (2024). Comprehensive Peri-Operative Risk Assessment and Management of Geriatric Patients. Diagnostics, 14. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    By increasing lean muscle mass, strength training elevates the RMR, leading to greater caloric expenditure even at rest.

    “By increasing lean muscle mass, strength training elevates the RMR, leading to greater caloric expenditure even at rest.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Zheng, L., Rao, Z., Wu, J., Ma, X., Jiang, Z., and Xiao, W. (2024). Resistance Exercise Improves Glycolipid Metabolism and Mitochondrial Biogenesis in Skeletal Muscle of T2DM Mice via miR-30d-5p/SIRT1/PGC-1α Axis. Int. J. Mol. Sci., 25. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationcitation

    These techniques create a robust platform for precision nutrition and enable tailored follow-ups, ensuring that interventions are dynamically aligned with individual goals.

    “These techniques create a robust platform for precision nutrition and enable tailored follow-ups, ensuring that interventions are dynamically aligned with individual goals [95].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Duan, 2021, Energy delivery guided by indirect calorimetry in critically ill patients: A systematic review and meta-analysis, Crit. Care source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    AI platforms integrate behavioral psychology principles, tracking adherence and identifying factors contributing to deviations.

    “AI platforms also integrate behavioral psychology principles, tracking adherence trends and identifying factors contributing to deviations.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [96] Kirk, D., Catal, C., and Tekinerdogan, B. (2021). Precision nutrition: A systematic literature review. Comput. Biol. Med., 133. source

      Not checked in the free run.

    • cites [97] Theodorakis, N., Feretzakis, G., Tzelves, L., Paxinou, E., Hitas, C., Vamvakou, G., Verykios, V.S., and Nikolaou, M. (2024). Integrating Machine Learning with Multi-Omics Technologies in Geroscience: Towards Personalized Medicine. J. Pers. Med., 14. source

      Not checked in the free run.

    • cites [98] Miyazawa, 2022, Artificial intelligence in food science and nutrition: A narrative review, Nutr. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When combined with aerobic exercise, a dual-modality approach maximizes fat oxidation, enhances cardiovascular health, and creates a synergistic effect that optimizes overall metabolic flexibility.

    “When combined with aerobic exercise, this dual-modality approach maximizes fat oxidation, enhances cardiovascular health, and creates a synergistic effect that optimizes overall metabolic flexibility [105].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Theodorakis, N., Nikolaou, M., Hitas, C., Anagnostou, D., Kreouzi, M., Kalantzi, S., Spyridaki, A., Triantafylli, G., Metheniti, P., and Papaconstantinou, I. (2024). Comprehensive Peri-Operative Risk Assessment and Management of Geriatric Patients. Diagnostics, 14. source

      Not checked in the free run.

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

    Study design and conductreasoning

    Variability in methodologies makes direct comparison across studies challenging.

    “The variability in methodologies—such as inconsistencies in defining and measuring BMR, hormonal fluctuations, and energy expenditure—makes direct comparison across studies challenging.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lifang Zheng et al. demonstrated that resistance exercise significantly improves glucose homeostasis, insulin signaling, and mitochondrial function in T2DM mice by downregulating miR-30d-5p, which targets SIRT1 and impacts PGC-1α expression.

    “Lifang Zheng et al. demonstrated that resistance exercise significantly improves glucose homeostasis, insulin signaling, and mitochondrial function in T2DM mice by downregulating miR-30d-5p, which targets SIRT1 and impacts PGC-1α expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Zheng, L., Rao, Z., Wu, J., Ma, X., Jiang, Z., and Xiao, W. (2024). Resistance Exercise Improves Glycolipid Metabolism and Mitochondrial Biogenesis in Skeletal Muscle of T2DM Mice via miR-30d-5p/SIRT1/PGC-1α Axis. Int. J. Mol. Sci., 25. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AI-powered platforms, wearable devices, and continuous glucose monitors enhance adherence by tracking biometrics and offering actionable insights to users, making weight management dynamic and adaptive to individual needs.

    “These tools enhance adherence by tracking biometrics and offering actionable insights to users, making weight management dynamic and adaptive to individual needs [96,97,98,99,100,101,102].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [96] Kirk, D., Catal, C., and Tekinerdogan, B. (2021). Precision nutrition: A systematic literature review. Comput. Biol. Med., 133. source

      Not checked in the free run.

    • cites [97] Theodorakis, N., Feretzakis, G., Tzelves, L., Paxinou, E., Hitas, C., Vamvakou, G., Verykios, V.S., and Nikolaou, M. (2024). Integrating Machine Learning with Multi-Omics Technologies in Geroscience: Towards Personalized Medicine. J. Pers. Med., 14. source

      Not checked in the free run.

    • cites [98] Miyazawa, 2022, Artificial intelligence in food science and nutrition: A narrative review, Nutr. Rev. source

      Not checked in the free run.

    • cites [99] Bond, 2023, Artificial intelligence & clinical nutrition: What the future might have in store, Clin. Nutr. ESPEN source

      Not checked in the free run.

    • cites [100] Theodore Armand, T.P., Nfor, K.A., Kim, J.I., and Kim, H.C. (2024). Applications of Artificial Intelligence, Machine Learning, and Deep Learning in Nutrition: A Systematic Review. Nutrients, 16. source

      Not checked in the free run.

    • cites [101] Sosa-Holwerda, A., Park, O.H., Albracht-Schulte, K., Niraula, S., Thompson, L., and Oldewage-Theron, W. (2024). The Role of Artificial Intelligence in Nutrition Research: A Scoping Review. Nutrients, 16. source

      Not checked in the free run.

    • cites [102] Zhu, J., and Wang, G. (2023). Artificial Intelligence Technology for Food Nutrition. Nutrients, 15. source

      Not checked in the free run.

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

    Premisecitation

    Incorporating resistance training, low-glycemic-index diets, and adequate sleep can prevent metabolic derangements associated with obesity.

    “For instance, incorporating resistance training, low-glycemic-index diets, and adequate sleep can prevent metabolic derangements associated with obesity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Dhanjani, S., Allen, H., Varman, B., Callender, C., Dave, J.M., and Thompson, D. (2024). Community-Based Participatory Obesity Prevention Interventions in Rural Communities: A Scoping Review. Nutrients, 16. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The intricate interplay of molecular and hormonal pathways shapes weight outcomes, challenging the conventional "calories in, calories out" model.

    “These findings underscore the intricate interplay of molecular and hormonal pathways in shaping weight outcomes, challenging the conventional “calories in, calories out” model.”
    Quote in the paperSubstantial claim
108 of 108

  • The paper relies on this without support.

    Effective weight management requires addressing individual metabolic and hormonal variability beyond the “calories in, calories out” model.

    “The global rise in obesity underscores the need for effective weight management strategies that address individual metabolic and hormonal variability, moving beyond the simplistic “calories in, calories out” model.”

  • The paper relies on this without support.

    Artificial intelligence and machine learning can identify patterns and predict metabolic responses to dietary and lifestyle modifications from genetic, hormonal, and lifestyle datasets.

    “By analyzing vast datasets—including genetic, hormonal, and lifestyle factors—AI can identify patterns and predict metabolic responses to various dietary and lifestyle modifications.”

  • The paper relies on this without support.

    Precision nutrition approaches can create individualized weight management strategies aligned with each person’s unique metabolic profile.

    “Precision approaches, such as nutrigenomics, indirect calorimetry, and artificial-intelligence-based strategies, can potentially leverage these insights to create individualized weight management strategies aligned with each person’s unique metabolic profile.”

  • The paper relies on this without support.

    Most precision medicine studies (nutrigenomics and ML models) are pilot-scale and lack validation in larger, diverse cohorts.

    “Despite promising advances in precision approaches, such as nutrigenomics and ML models, most studies are pilot-scale and lack validation in larger, diverse cohorts.”

  • The paper relies on this without support.

    Precision approaches often suffer from high costs, which can hinder practical implementation in clinical settings.

    “Furthermore, these approaches often suffer from high costs, which can hinder practical implementation in clinical settings.”

  • The paper relies on this without support.

    The majority of the literature emphasizes short-term interventions, such as caloric restriction or overfeeding studies, without sufficient exploration of long-term sustainability and the persistence of metabolic adaptations over time.

    “The majority of the literature emphasizes short-term interventions, such as caloric restriction or overfeeding studies, without sufficient exploration of long-term sustainability and the persistence of metabolic adaptations over time.”

  • The paper relies on this without support.

    Hypocaloric diets often fail to address the adaptive responses that hinder long-term success, such as metabolic slowdown and hormonal dysregulation.

    “While hypocaloric diets are a cornerstone of obesity management, they often fail to address the adaptive responses that hinder long-term success, such as metabolic slowdown and hormonal dysregulation.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • During the weight maintenance phase, weight regain can occur secondary to decreased energy expenditure and increased energy efficiency, which together result in a net decrease in caloric needs.

    “During the weight maintenance phase, weight regain can occur secondary to decreased energy expenditure and increased energy efficiency, which together result in a net decrease in caloric needs5–8.”

    From Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial (2026) · cites this paper as [8]

  • Increased cortisol stimulates muscle proteolysis through the ubiquitin-proteasome pathway and antagonizes insulin's anabolic effects, further contributing to lean mass loss.

    “Increased cortisol stimulates muscle proteolysis through the ubiquitin-proteasome pathway and antagonizes insulin’s anabolic effects, further contributing to lean mass loss [32].”

    From Muscle loss and GLP-1R agonists use (2025) · cites this paper as [32]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • HDL effect estimate has the opposite sign from its confidence interval

    Minor

    The reported HDL cholesterol difference is positive (2.24 mg/dL), but its entire 95% confidence interval is negative. An effect estimate cannot lie outside its own confidence interval, so at least one of these conclusion-bearing values has the wrong sign.

1 of 1

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Authors
Theodorakis, N., Kreouzi, M., Pappas, A., & Nikolaou, M.
Affiliations
  • National and Kapodistrian University of Athens (GR)
  • Simanogleio-Amalia Fleming General Hospital (GR)
Corresponding author
Nikolaou, Maria
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2024-12-15
Volume
25
Issue
24
Pages
13438
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms252413438
PMC
PMC11676201
OpenAlex
W4405418556
Semantic Scholar
19b98022be02354f5c84c6529661a2058ed657a3
Cited by
43
References
107
Citations by year
2026: 22 · 2025: 21
FWCI
2.39
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
  • Health Sciences › Medicine › Physiology › Body Composition Measurement Techniques
Keywords
weight management, obesity, somatotype, metabolic adaptation, hormonal adaptation, genetic polymorphism, epigenetics, lipogenesis, myofibrillar protein synthesis, lipolysis, muscle protein degradation, resting metabolic rate, caloric restriction, overfeeding, personalized nutrition, nutrigenomics, indirect calorimetry, artificial intelligence
MeSH terms
Adaptation, Physiological, Animals, Energy Intake, Energy Metabolism, Hormones, Humans, Obesity, Exercise

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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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