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Cited by 112Mitochondrial Function and PathologyAdipose Tissue and MetabolismMetabolism, Diabetes, and Cancer

Defects in mitochondrial efficiency and H2O2 emissions in obese women are restored to a lean phenotype with aerobic exercise training

Open access
Konopka, Adam R., Asante, Albert, Lanza, Ian R., Robinson, Matthew M., Johnson, Matthew L., Dalla Man, Chiara, Cobelli, Claudio, Amols, Mark H. +2 more·2015·Diabetes
DOI 10.2337/db14-1701PMC PMC4439568
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Abstract

The notion that mitochondria contribute to obesity-induced insulin resistance is highly debated. Therefore, we determined whether obese (BMI 33 kg/m2), insulin-resistant women with polycystic ovary syndrome had aberrant skeletal muscle mitochondrial physiology compared with lean, insulin-sensitive women (BMI 23 kg/m2). Maximal whole-body and mitochondrial oxygen consumption were not different between obese and lean women. However, obese women exhibited lower mitochondrial coupling and phosphorylation efficiency and elevated mitochondrial H2O2 (mtH2O2) emissions compared with lean women. We further evaluated the impact of 12 weeks of aerobic exercise on obesity-related impairments in insulin sensitivity and mitochondrial energetics in the fasted state and after a high-fat mixed meal. Exercise training reversed obesity-related mitochondrial derangements as evidenced by enhanced mitochondrial bioenergetics efficiency and decreased mtH2O2 production. A concomitant increase in catalase antioxidant activity and decreased DNA oxidative damage indicate improved cellular redox status and a potential mechanism contributing to improved insulin sensitivity. mtH2O2 emissions were refractory to a high-fat meal at baseline, but after exercise, mtH2O2 emissions increased after the meal, which resembles previous findings in lean individuals. We demonstrate that obese women exhibit impaired mitochondrial bioenergetics in the form of decreased efficiency and impaired mtH2O2 emissions, while exercise effectively restores mitochondrial physiology toward that of lean, insulin-sensitive individuals.

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Registry

Crossref · 10.2337/db14-1701

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 46 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Protein carbonyl content increased with SED.

    “Moreover, the protein carbonyl content, an indicator of protein oxidative damage, was maintained after AET but increased (P < 0.05) with SED (Fig. 4C).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The level of protein carbonyls, a marker of protein oxidation, stayed unchanged after AET.

    “Moreover, the protein carbonyl content, an indicator of protein oxidative damage, was maintained after AET but increased (P < 0.05) with SED (Fig. 4C).”
    Quote in the paperNot a substantial claim
  • Findingown data

    State 4 respiration was higher in obese women than in lean women.

    “However, state 4 respiration was greater in obese individuals, indicating increased oxygen consumption not linked with phosphorylation, which is consistent with decreased (P < 0.05) mitochondrial coupling efficiency in the form of reduced RCR (Fig. 2D).”
    Quote in the paperSubstantial claim
  • Findingown data

    SED did not alter any mitochondrial parameters.

    “SED did not alter any mitochondrial parameters.”
    Quote in the paperSubstantial claim
  • Findingown data

    AET increased RCR and ADP:O in obese women.

    “RCR and ADP:O increased (P < 0.05) after AET (Fig. 3F and G) and were no longer different from lean women.”
    Quote in the paperSubstantial claim
  • May combine two claims. 29
  • The quote only partly states this claim. 4
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data

    After adjustment for age, obese women still had lower RCR and ADP:O and higher mtH2O2 emissions than lean insulin-sensitive women.

    “Moreover, after adjustment for age, obese women still exhibit mitochondrial derangements evidenced from lower bioenergetics efficiency (decreased RCR and ADP:O) and elevated mtH2O2 emissions compared with lean, insulin-sensitive women.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Twelve weeks of AET increased maximal citrate synthase activity in obese women.

    “AET increased (P < 0.05) VO2 peak (Fig. 3A) and maximal citrate synthase activity (Fig. 3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AET decreased mtH2O2 emission from isolated mitochondria in the fasted state in obese women, reaching levels similar to lean women.

    “The H2O2-emitting potential of isolated mitochondria in the fasted condition was decreased (P < 0.05) after AET, achieving levels similar to those in lean women (Fig. 3H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Before intervention, the SED and AET obese groups were similar in weight, BMI, whole-body fat, FFM, age, fasting insulin, fasting glucose, and HOMA.

    “Baseline characteristics of body weight, BMI, whole-body fat, FFM, age, and plasma concentrations of insulin and glucose as well as HOMA were not different between SED and AET obese women but were greater than in lean women (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Before intervention, obese women had higher weight, BMI, whole-body fat, FFM, age, fasting insulin, fasting glucose, and HOMA than lean women.

    “Baseline characteristics of body weight, BMI, whole-body fat, FFM, age, and plasma concentrations of insulin and glucose as well as HOMA were not different between SED and AET obese women but were greater than in lean women (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At baseline, a high-fat meal did not change mtH2O2 emissions, whereas after exercise training mtH2O2 emissions rose after the meal, similar to prior observations in lean people.

    “mtH2O2 emissions were refractory to a high-fat meal at baseline, but after exercise, mtH2O2 emissions increased after the meal, which resembles previous findings in lean individuals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the SED group, BMI, weight, and whole-body fat rose over the 12 weeks.

    “BMI, weight, and whole body fat were increased after 12 weeks in the SED group but were maintained at baseline values after 12 weeks of AET (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    After 12 weeks of AET, BMI, weight, and whole-body fat remained at baseline levels.

    “BMI, weight, and whole body fat were increased after 12 weeks in the SED group but were maintained at baseline values after 12 weeks of AET (Table 2).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Twelve weeks of aerobic exercise training increased VO2 peak in obese women.

    “AET increased (P < 0.05) VO2 peak (Fig. 3A) and maximal citrate synthase activity (Fig. 3B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SED did not alter antioxidant activity or DNA oxidative damage.

    “Antioxidant activity and DNA oxidative damage were not different with SED.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Insulin sensitivity after the mixed-meal tolerance test increased over time, mainly due to improvements after AET (interaction P = 0.06).

    “Insulin sensitivity after the mixed-meal tolerance test increased with time (P < 0.05), which was driven mainly by improvements after AET (P = 0.06 interaction) (Fig. 5B).”
    • Also stated in: § Exercise Improves Insulin Sensitivity · hedged
      “A similar trend (P = 0.06) was observed for postprandial insulin sensitivity using the oral minimal model (B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Insulin sensitivity is lower in obese women even though their mitochondrial oxidative capacity is similar to that of lean controls.

    “In the current study, we show that insulin sensitivity is lower in obese women in spite of mitochondrial oxidative capacity similar to that in lean control subjects.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The lean women studied are a valid reference for a normal lean phenotype.

  • May combine two claims.

    Findingown data

    After training, a high-fat meal raised mtH2O2 emissions in obese women, alongside better postprandial insulin sensitivity and glucose tolerance.

    “In the trained state, high-fat feeding increased mtH2O2 emissions in obese women, and this change in mtH2O2 production and plausibly metabolic flexibility occurred concurrently with improvements in postprandial insulin sensitivity and glucose tolerance.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mitochondrial H2O2 emissions measured in isolated mitochondria reflect in vivo mitochondrial H2O2 production.
    • Rests on an assumption: A high-fat mixed meal is a valid stimulus for assessing metabolic flexibility at the mitochondrial level.

  • May combine two claims.

    Findingown data

    AET improved citrate synthase activity and oxidative capacity.

    “AET enhanced mitochondrial bioenergetics efficiency, correcting the impairment in obese women, and improved citrate synthase activity and oxidative capacity, which is consistent with classical mitochondrial adaptations (40–44).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 12-week aerobic exercise training program is a realistic and sufficient intervention to induce mitochondrial adaptations in obese women.

  • The quote only partly states this claim.

    Findingown data

    Twelve weeks of exercise training increased mitochondrial bioenergetics efficiency.

    “In the current study, 12 weeks of exercise training in obese women not only increased insulin sensitivity but also reduced mtH2O2 emission and increased mitochondrial bioenergetics efficiency.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 12-week aerobic exercise training program is a realistic and sufficient intervention to induce mitochondrial adaptations in obese women.

  • May combine two claims.

    Findingown data

    The women remained obese and lost only minimal, nonsignificant weight after exercise training.

    “It is important to note that this enhancement of insulin sensitivity and mitochondrial remodeling occurred despite the fact that these women remained obese and lost only minimal (nonsignificant) weight after exercise training.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After exercise training, women with PCOS showed substantial improvements in mtH2O2 production, coupling efficiency, catalase activity, and DNA oxidative damage.

    “Consistent with this hypothesis, we found evidence that women with PCOS, who are inherently insulin resistant, exhibit marked improvements in mtH2O2 production, coupling efficiency, catalase activity, and DNA oxidative damage after exercise training.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mitochondrial H2O2 emissions measured in isolated mitochondria reflect in vivo mitochondrial H2O2 production.
    • Rests on an assumption: The 12-week aerobic exercise training program is a realistic and sufficient intervention to induce mitochondrial adaptations in obese women.

  • May combine two claims.

    Findingown data

    Citrate synthase and SDH were increased after training.

    “SDH is an enzyme common to both the TCA cycle and electron transport chain and, accordingly, our study found that citrate synthase and SDH, both involved in the TCA cycle, were increased after training, indicating increased maximal capacity for TCA cycle flux in obese women.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AET improved mitochondrial bioenergetics efficiency, reversing the defect in obese women.

    “AET enhanced mitochondrial bioenergetics efficiency, correcting the impairment in obese women, and improved citrate synthase activity and oxidative capacity, which is consistent with classical mitochondrial adaptations (40–44).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 12-week aerobic exercise training program is a realistic and sufficient intervention to induce mitochondrial adaptations in obese women.

  • The quote only partly states this claim.

    Findingown data

    Twelve weeks of exercise training reduced mtH2O2 emission.

    “In the current study, 12 weeks of exercise training in obese women not only increased insulin sensitivity but also reduced mtH2O2 emission and increased mitochondrial bioenergetics efficiency.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mitochondrial H2O2 emissions measured in isolated mitochondria reflect in vivo mitochondrial H2O2 production.
    • Rests on an assumption: The 12-week aerobic exercise training program is a realistic and sufficient intervention to induce mitochondrial adaptations in obese women.

  • May combine two claims.

    Interpretationown data

    Obese women show defective mitochondrial bioenergetics, with lower efficiency and altered mtH2O2 release, and exercise largely returns mitochondrial physiology toward the lean insulin-sensitive profile.

    “We demonstrate that obese women exhibit impaired mitochondrial bioenergetics in the form of decreased efficiency and impaired mtH2O2 emissions, while exercise effectively restores mitochondrial physiology toward that of lean, insulin-sensitive individuals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    AET reversed the obesity-linked mitochondrial abnormalities, reflected by better bioenergetic efficiency and lower mtH2O2 output.

    “Exercise training reversed obesity-related mitochondrial derangements as evidenced by enhanced mitochondrial bioenergetics efficiency and decreased mtH2O2 production.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    After AET, higher catalase activity together with less DNA oxidative damage point to a better cellular redox state and may partly explain the improved insulin sensitivity.

    “A concomitant increase in catalase antioxidant activity and decreased DNA oxidative damage indicate improved cellular redox status and a potential mechanism contributing to improved insulin sensitivity.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Amplex Red fluorescence readings were adjusted for background auto-oxidation and converted using a standard curve.

    “The fluorescent signal was corrected for background auto-oxidation and calibrated to a standard curve.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    A single AET participant was removed from analysis after not finishing the whole meal.

    “One participant in the exercise group was excluded owing to failure to complete the entire meal.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The outer mitochondrial membrane integrity was checked by adding cytochrome c.

    “Cytochrome c (cyto c) was added at 10 μmol/L to assess integrity of the outer mitochondrial membrane.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The hyperinsulinemic-euglycemic clamp was performed approximately 71 h after the last exercise bout.

    “The clamp was completed in a subset of obese women (AET = 8, SED = 7) and performed ∼71 h after the last exercise bout.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The authors also compared groups after accounting for the age difference.

    “Group comparisons were also made after adjustment for difference in age between groups.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Obese women were randomized to AET or SED.

    “Obese women were randomized and studied before and after 12 weeks of AET (n = 12) or SED (n = 13).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To verify that oxygen use came from mitochondria, antimycin A was added.

    “Last, 2.5 μmol/L antimycin A was added to inhibit mitochondrial oxygen consumption to confirm that oxygen consumption was of mitochondrial origin.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Changes in mitochondrial physiology have been proposed as a cause of skeletal muscle insulin resistance and metabolic inflexibility, because some studies report lower mitochondrial content and/or oxidative capacity in insulin-resistant or type 2 diabetic people.

    “Altered mitochondrial physiology is implicated in the etiology of skeletal muscle insulin resistance and metabolic inflexibility owing to reports of reduced mitochondrial content and/or oxidative capacity in individuals who are insulin resistant or have type 2 diabetes (2–5).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [2] Kelley, 2002, Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes, Diabetes source

      Not checked in the free run.

    • cites [3] Ritov, 2010, Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

    • cites [4] Petersen, 2003, Mitochondrial dysfunction in the elderly: possible role in insulin resistance, Science source

      Not checked in the free run.

    • cites [5] Petersen, 2004, Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes, N Engl J Med source

      Not checked in the free run.

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

    Premisecitation

    One recent study found no difference in mitochondrial oxidative capacity but higher mtH2O2 release in obese insulin-resistant compared with lean insulin-sensitive people, suggesting oxidative stress rather than capacity contributes to obesity-related insulin resistance.

    “A recent report (10) indicated that mitochondrial oxidative capacity was not different, but mitochondrial hydrogen peroxide (mtH2O2) emissions were elevated in obese, insulin resistant versus lean, insulin-sensitive individuals, thus positing mitochondrial oxidative stress rather than oxidative capacity as a contributor of obesity-induced insulin resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Fisher-Wellman, 2014, Mitochondrial respiratory capacity and content are normal in young insulin-resistant obese humans, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Caloric restriction is known to improve insulin sensitivity and lessen mitochondrial redox stress, which lowers reactive oxygen species release.

    “Thus, energy restriction that is well-known to enhance insulin sensitivity also reduces redox burden on the mitochondria, resulting in lower reactive oxygen species emissions (15).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Lanza, 2012, Chronic caloric restriction preserves mitochondrial function in senescence without increasing mitochondrial biogenesis, Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Women with PCOS typically have obesity and marked insulin resistance, yet their skeletal muscle mitochondrial respiration is preserved relative to BMI-matched controls.

    “we chose to study women with polycystic ovary syndrome (PCOS) because these women present clinically with obesity and severe insulin resistance but preserved skeletal muscle mitochondrial respiration compared with BMI-matched control subjects (19,20)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Rabøl, 2011, Skeletal muscle mitochondrial function in polycystic ovarian syndrome, Eur J Endocrinol source

      Not checked in the free run.

    • cites [20] Eriksen, 2011, Intact primary mitochondrial function in myotubes established from women with PCOS, J Clin Endocrinol Metab source

      Not checked in the free run.

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

    Study design and conductreasoning

    The muscle biopsy samples were taken about 94 and 99 h after the final exercise session.

    “Therefore, muscle biopsies were obtained ∼94 and 99 h after the last exercise bout (study day B).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Anderson et al. showed a connection among energy balance, mitochondrial redox state, and insulin sensitivity.

    “Anderson et al. (18) convincingly established a link between energy balance, mitochondrial redox state, and insulin sensitivity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Anderson, 2009, Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans, J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise increases electron transport coupling efficiency, complete β-oxidation, and TCA cycle enzymes.

    “Indeed, we and others have shown that exercise increases electron transport coupling efficiency (current study), complete β-oxidation (28,46), and TCA cycle enzymes (47), including citrate synthase, SDH, and isocitrate dehydrogenase, which may collectively alleviate the metabolic bottleneck and metabolite accumulation during nutrient stress.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [28] Battaglia, 2012, Effect of exercise training on metabolic flexibility in response to a high-fat diet in obese individuals, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

    • cites [46] Koves, 2005, Peroxisome proliferator-activated receptor-γ co-activator 1α-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency, J Biol Chem source

      Not checked in the free run.

    • cites [47] Lanza, 2008, Endurance exercise as a countermeasure for aging, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is an association between mtH2O2 emissions and both insulin resistance and metabolic inflexibility.

    “Collectively, these findings suggest that mtH2O2 emissions are associated with insulin resistance and metabolic inflexibility.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mitochondrial H2O2 emissions measured in isolated mitochondria reflect in vivo mitochondrial H2O2 production.

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

    Study design and conductown data

    There was a statistical difference in age between the obese and lean women.

    “Even though the obese and lean women were both young (35 vs. 25 years old), there was a statistical difference in age.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Prior obesity models suggest that β-oxidation exceeds TCA cycle capacity, causing buildup of acetyl-CoA, acylcarnitine esters, and mtH2O2.

    “These data may have important implications, as previous models of obesity have indicated that β-oxidation outpaces TCA cycle, leading to accumulation of acetyl-CoA, acylcarnitine esters, and mtH2O2 (16,45,46).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Muoio, 2012, Lipid-induced mitochondrial stress and insulin action in muscle, Cell Metab source

      Not checked in the free run.

    • cites [45] Koves, 2008, Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance, Cell Metab source

      Not checked in the free run.

    • cites [46] Koves, 2005, Peroxisome proliferator-activated receptor-γ co-activator 1α-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency, J Biol Chem source

      Not checked in the free run.

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

    Premisecitation

    Exercise-induced improvements in insulin sensitivity arise from many different alterations.

    “Improvements in insulin sensitivity with exercise are induced by a myriad of alterations (34–37), while our data suggest that improvements in cellular redox status play a prominent role.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [34]

      Not checked in the free run.

    • cites [35] Perseghin, 1996, Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects, N Engl J Med source

      Not checked in the free run.

    • cites [36] Coen, 2012, Role of intramyocelluar lipids in human health, Trends Endocrinol Metab source

      Not checked in the free run.

    • cites [37] Schenk, 2007, Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance, J Clin Invest source

      Not checked in the free run.

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

    Premisecitation

    A single H2O2 dose can enhance insulin-stimulated glucose uptake.

    “Indeed, an acute dose of H2O2 can increase insulin-stimulated glucose uptake (39), consistent with the findings in the current study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Higaki, 2008, Oxidative stress stimulates skeletal muscle glucose uptake through a phosphatidylinositol 3-kinase-dependent pathway, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

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

    Premisecitation

    Lipid stress may cause mitochondrial uncoupling, possibly via uncoupling protein 3.

    “The mechanisms underlying detriments in mitochondrial efficiency are not certain; however, lipid stress can evoke mitochondrial uncoupling potentially through uncoupling protein 3 (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Anderson, 2007, Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid-supported respiration, J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    In obese women, oxygen consumption appeared poorly coupled to phosphorylation and might involve proton leak across the inner mitochondrial membrane.

    “Obese women had greater oxygen consumption during oligomycin-supported state 4 respiration, suggesting that oxygen consumption was not well coupled to phosphorylation and may be related to proton leak across the inner mitochondrial membrane.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Exercise changed the obesity-linked mitochondrial energetic defects, restoring functional parameters to those of lean, insulin-sensitive women.

    “Therefore, exercise altered the obesity-related defects in mitochondrial energetics, correcting these functional parameters to values observed in lean, insulin-sensitive women.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The lean women studied are a valid reference for a normal lean phenotype.
    • Rests on an assumption: The 12-week aerobic exercise training program is a realistic and sufficient intervention to induce mitochondrial adaptations in obese women.

  • May combine two claims.

    Premisecitation

    A nutrient surplus generates a positive mitochondrial membrane potential, raising mtH2O2 emissions.

    “The nutrient burden creates a positive mitochondrial membrane potential, which increases mtH2O2 emissions (17), and chronic exposure to reactive oxygen species has been shown to inhibit insulin-mediated GLUT4 translocation (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Fisher-Wellman, 2012, Linking mitochondrial bioenergetics to insulin resistance via redox biology, Trends Endocrinol Metab source

      Not checked in the free run.

46 of 46

  • The paper relies on this without support.

    Aerobic exercise training raises energy expenditure and improves insulin sensitivity.

    “Although compelling evidence strongly links mitochondrial redox balance in the etiology of insulin resistance, it remains to be determined whether aerobic exercise training (AET) that is known to increase energy expenditure and insulin sensitivity alters skeletal muscle mtH2O2 production under different states (i.e., postprandial and postabsorptive).”

  • The paper relies on this without support.

    Results from obese women with PCOS can be generalized to obese insulin-resistant women without PCOS.

    “we chose to study women with polycystic ovary syndrome (PCOS) because these women present clinically with obesity and severe insulin resistance but preserved skeletal muscle mitochondrial respiration compared with BMI-matched control subjects (19,20)”

  • The paper relies on this without support.

    Mitochondrial H2O2 emissions measured in isolated mitochondria reflect in vivo mitochondrial H2O2 production.

    “mtH2O2 emissions were evaluated in isolated mitochondria during state 2 conditions.”

  • The paper relies on this without support.

    The lean women studied are a valid reference for a normal lean phenotype.

    “obese, insulin-resistant women with PCOS exhibit mitochondrial derangements in the form of lower bioenergetics efficiency and increased mtH2O2 emissions and that exercise training reversed these derangements to resemble a lean phenotype.”

  • The paper relies on this without support.

    The obese women with PCOS are representative of obese insulin-resistant women generally.

    “The current study shows that obese, insulin-resistant women with PCOS exhibit mitochondrial derangements in the form of lower bioenergetics efficiency and increased mtH2O2 emissions and that exercise training reversed these derangements to resemble a lean phenotype.”

  • The paper relies on this without support.

    The 12-week aerobic exercise training program is a realistic and sufficient intervention to induce mitochondrial adaptations in obese women.

    “We show that a realistic, short-term exercise program not only improves skeletal muscle mitochondrial oxidative capacity but also normalizes the impairments in mitochondrial efficiency and oxidant emission, increases activity of endogenous antioxidant systems, and decreases cellular oxidative damage.”

  • The paper relies on this without support.

    A high-fat mixed meal is a valid stimulus for assessing metabolic flexibility at the mitochondrial level.

    “After AET, there was a change in the relationship among a single high-fat mixed meal, mtH2O2 emissions, and insulin sensitivity.”

  • The paper relies on this without support.

    The presence of PCOS does not independently affect mitochondrial parameters beyond obesity and insulin resistance.

    “obese, insulin-resistant women with PCOS exhibit mitochondrial derangements in the form of lower bioenergetics efficiency and increased mtH2O2 emissions and that exercise training reversed these derangements to resemble a lean phenotype.”
8 of 8

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?

  • In women with insulin resistance, abnormal mtH2O2 emission normalized by aerobic exercise training improved insulin sensitivity.

    “In women with IR, abnormal mtH2O2 emission when normalized by aerobic exercise training improved insulin sensitivity (4).”

    From TFAM Enhances Fat Oxidation and Attenuates High-Fat Diet–Induced Insulin Resistance in Skeletal Muscle (2019) · cites this paper as [4]

    The Discussion reports that aerobic exercise normalized elevated mtH2O2 emissions and improved insulin sensitivity in obese, insulin-resistant women with PCOS. It describes the mitochondrial changes as likely contributors, rather than establishing that normalized emissions caused the improvement in insulin sensitivity. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • To our knowledge, it is the first time data from 10 of the trials included in this systematic review have been meta-analysed, suggesting that this is the most comprehensive and up-to-date systematic review on exercise in the treatment of women with PCOS.

    “To our knowledge, it is the first time data from 10 of the trials included in this systematic review have been meta-analysed [32, 34, 102, 104, 108–110, 117, 119] suggesting that this is the most comprehensive and up-to-date systematic review on the topic of exercise in the treatment of women with PCOS.”

    From Exercise, or exercise and diet for the management of polycystic ovary syndrome: a systematic review and meta-analysis (2019) · cites this paper as [102]

  • Women with polycystic ovarian syndrome are insulin-resistant, but their muscle has similar maximal mitochondrial oxygen flux to insulin-sensitive lean women, despite lower mitochondrial coupling and phosphorylation efficiencies and higher reactive oxygen species emission.

    “Women with PCOS are insulin-resistant, but their muscle has similar maximal mitochondrial oxygen flux to insulin-sensitive lean women's, despite displaying lower mitochondrial coupling and phosphorylation efficiencies and higher ROS emission (99).”

    From Altered mitochondrial function in insulin-deficient and insulin-resistant states (2018) · cites this paper as [99]

  • Twelve weeks of aerobic exercise training corrects mitochondrial abnormalities and improves insulin sensitivity in women with polycystic ovarian syndrome.

    “Moreover, 12 weeks of aerobic exercise training corrected mitochondrial abnormalities besides improving insulin sensitivity in women with PCOS (99).”

    From Altered mitochondrial function in insulin-deficient and insulin-resistant states (2018) · cites this paper as [99]

  • In obese, insulin-resistant women with polycystic ovarian syndrome, 12 weeks of aerobic exercise increases mitochondrial respiration and coupling efficiency while decreasing reactive oxygen species emission and irreversible DNA damage toward levels of lean, insulin-sensitive individuals.

    “As mentioned above, in obese, insulin-resistant women with PCOS, 12 weeks of aerobic exercise increased mitochondrial respiration and coupling efficiency while decreasing ROS emission and irreversible DNA damage toward those of lean, insulin-sensitive individuals (99).”

    From Altered mitochondrial function in insulin-deficient and insulin-resistant states (2018) · cites this paper as [99]

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.

  • Lean-group BMI differs between the abstract and Table 1

    Minor

    The abstract gives the lean group a BMI of 23 kg/m2, while Table 1 reports 24 ± 1 kg/m2 for the same group.

  • Oligomycin concentration differs by a factor of 1,000

    Minor

    The Figure 3 caption specifies 2 μg/μL for the permeabilized-fiber experiment, whereas the methods specify 2 μg/mL for that experiment.

2 of 2

Cites

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2 of the 50 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Konopka, A. R., Asante, A., Lanza, I. R., Robinson, M. M., Johnson, M. L., Dalla Man, C., Cobelli, C., Amols, M. H., Irving, B. A., & Nair, K. S.
Affiliations
  • Mayo Clinic (US)
  • Department of Information Engineering, University of Padova, Padova, Italy
  • University of Padua (IT)
Corresponding author
Nair, K.S.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2015-01-13
Volume
64
Issue
6
Pages
2104-2115
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db14-1701
PMC
PMC4439568
OpenAlex
W1989373047
Cited by
112
References
50
Citations by year
2026: 8 · 2025: 5 · 2024: 6 · 2023: 12 · 2022: 13 · 2021: 16 · 2020: 12 · 2019: 9 · 2018: 5 · 2017: 11 · 2016: 9 · 2015: 6
FWCI
4.48
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/site/license (vor, 322 d)
Locations
  • Diabetes (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Civil War Book Review (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK41973, T32DK007352, U24DK100469)
  • National Center for Advancing Translational Sciences (KL2RR024151, KL2TR000136, UL1TR000135)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
mitochondrial efficiency, obesity, insulin resistance, polycystic ovary syndrome, aerobic exercise training, skeletal muscle mitochondria, mitochondrial coupling, mitochondrial phosphorylation, mitochondrial bioenergetics, catalase, oxidative DNA damage, redox state, women
MeSH terms
Estradiol, Female, Humans, Hydrogen Peroxide, Insulin Resistance, Mitochondria, Obesity, Oxygen Consumption, Progesterone, Thinness, Exercise, Oxidative Stress

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 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

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

What counts as a claim ›How we measure confidence ›How we check this ›

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