CoChat
Sign Up
Cited by 138Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismLipid metabolism and biosynthesis

Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused?

Open access
Muoio, Deborah M.·2010·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
DOI 10.1016/j.bbalip.2009.11.007PMC PMC4428562
Open this paper in CoChat — free account

Abstract

The term lipotoxicity elicits visions of steatotic liver, fat laden skeletal muscles and engorged lipid droplets that spawn a number of potentially harmful intermediates that can wreak havoc on signal transduction and organ function. Prominent among these so-called lipotoxic mediators are signaling molecules such as long chain acyl-CoAs, ceramides and diacyglycerols; each of which is thought to engage serine kinases that disrupt the insulin signaling cascade, thereby causing insulin resistance. Defects in skeletal muscle fat oxidation have been implicated as a driving factor contributing to systemic lipid imbalance, whereas exercise-induced enhancement of oxidative potential is considered protective. The past decade of diabetes research has focused heavily on the foregoing scenario, and indeed the model is grounded in strong experimental evidence, albeit largely correlative. This review centers on mechanisms that connect lipid surplus to insulin resistance in skeletal muscle, as well as those that underlie the antilipotoxic actions of exercise. Emphasis is placed on recent studies that challenge accepted paradigms.

Integrity signals

Registry

Crossref · 10.1016/j.bbalip.2009.11.007

Cites

98 of 98 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 126 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    The athletes' paradox indicates that intramuscular lipid droplet accumulation by itself is not sufficient to disrupt insulin action.

    “This phenomenon, now well known as the “athletes' paradox”, suggested that lipid droplet accumulation per se is not sufficient to disrupt insulin action.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Cross-sectional studies show that isolated muscle strips, tissue homogenates, or cultured myocytes from severely obese and/or diabetic humans oxidize fat more slowly than specimens from healthy controls.

    “cross-sectional studies showing that isolated muscle strips, tissue homogenates or cultured myocytes from severely obese and/or diabetic humans exhibit diminished rates of fat oxidation when compared to specimens derived from healthy control subjects [9,41,46,87].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [9] Blaak, 2004, Basic disturbances in skeletal muscle fatty acid metabolism in obesity and type 2 diabetes mellitus, Proc. Nutr. Soc. source

      Not checked in the free run.

    • cites [41] Hulver, 2003, Skeletal muscle lipid metabolism with obesity, Am. J. Physiol. Endocrinol. Metab. source

      Not checked in the free run.

    • cites [46] Kelley, 1999, Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss, Am. J. Physiol.

      Not checked in the free run.

    • cites [87] Ukropcova, 2005, Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donor, J. Clin. Invest. source

      Not checked in the free run.

  • Premisecitation

    Highly insulin-sensitive endurance athletes can have intramuscular lipid droplet accumulation equal to or greater than that in type 2 diabetes patients.

    “reports showing that lipid droplet accumulation in highly insulin-sensitive endurance athletes is similar to or even greater than that found in patients with type 2 diabetes [27,89,90].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Goodpaster, 2001, Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

    • cites [89] van Loon, 2006, Increased intramuscular lipid storage in the insulin-resistant and endurance-trained state, Pflugers Arch. source

      Not checked in the free run.

    • cites [90] van Loon, 2004, Intramyocellular lipid content in type 2 diabetes patients compared with overweight sedentary men and highly trained endurance athletes, Am. J. Physiol. Endocrinol. Metab. source

      Not checked in the free run.

  • Interpretationreasoning

    A limitation in oxidative capacity or β-oxidation requires a compensatory rise in glucose uptake and glycolytic ATP production.

    “Conversely, a generalized limitation in oxidative capacity or a specific impingement of β-oxidation necessitates a compensatory increase in glucose uptake and glycolytic ATP production.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Diet-induced and genetic glucose intolerance are associated with high rates of incomplete fat oxidation.

    “diet-induced and genetic forms of glucose intolerance were associated with high rates of incomplete fat oxidation [49,50]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] Koves, 2005, Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-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 [50] Koves, 2008, Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance, Cell Metab. source

      Not checked in the free run.

  • May combine two claims. 43
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Interpretationnone given

    The lipotoxicity model linking lipid surplus to skeletal muscle insulin resistance rests on strong experimental evidence, but that evidence is mostly correlative.

    “The past decade of diabetes research has focused heavily on the foregoing scenario, and indeed the model is grounded in strong experimental evidence, albeit largely correlative.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The inverse relationship between intramuscular triacylglycerol and insulin sensitivity appears in obese and diabetic humans and in rodent and cell-culture models of metabolic disease or chronic lipid exposure.

    “This relationship is evident in obese and diabetic humans as well as in several rodent and cell culture models of metabolic disease and/or chronic lipid exposure [3,40,41].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] An, 2004, Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance, Nat. Med. source

      Not checked in the free run.

    • cites [40] Hulver, 2005, Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans, Cell Metab. source

      Not checked in the free run.

    • cites [41] Hulver, 2003, Skeletal muscle lipid metabolism with obesity, Am. J. Physiol. Endocrinol. Metab. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Intramuscular triacylglycerol content is strongly inversely associated with insulin sensitivity.

    “Interest in this topic grew from numerous reports describing a strong negative association between IMTG content and insulin sensitivity [28].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Goodpaster, 2002, Skeletal muscle triglyceride: marker or mediator of obesity-induced insulin resistance in type 2 diabetes mellitus?, Curr. Diab. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle insulin resistance often coexists with mitochondrial abnormalities, including altered morphology, lower NADH:O2 oxidoreductase activity, reduced in vivo ATP synthesis and TCA cycle flux, and low expression of mitochondrial biogenesis and oxidative metabolism genes.

    “muscle insulin resistance often (but not always [86]) coexists with abnormalities in mitochondrial morphology, reduced NADH:O2 oxidoreductase activity, diminished in vivo rates of ATP synthesis and TCA cycle flux, as well as low expression levels of genes involved in mitochondrial biogenesis and oxidative metabolism [47,49,59,68,78].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [47] Kelley, 2002, Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes, Diabetes source

      Not checked in the free run.

    • cites [49] Koves, 2005, Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-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 [59] Mootha, 2003, PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes, Nat. Genet. source

      Not checked in the free run.

    • cites [68] Patti, 2003, Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1, Proc. Natl. Acad. Sci. U.S. A. source

      Not checked in the free run.

    • cites [78] Ritov, 2005, Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes, Diabetes source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The mitochondrial dysfunction theory of insulin resistance predicts that inadequate mitochondrial fatty acid uptake and oxidation diverts fatty acids into producing harmful lipid signaling molecules.

    “the mitochondrial dysfunction theory of insulin resistance predicts that impaired or insufficient mitochondrial uptake and oxidation of fatty acids results in their alternative use as substrates for generating harmful lipid signaling molecules [69].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Petersen, 2006, New insights into the pathogenesis of insulin resistance in humans using magnetic resonance spectroscopy, Obesity (Silver Spring) source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    At rest, ATP demand is low and the electron transport system operates at only a small fraction of total respiratory capacity.

    “Under resting conditions ATP demands are low and the ETS operates at only a small fraction of total respiratory capacity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The idea that impaired fat oxidation causes glucose intolerance and high fat oxidation promotes glucose uptake conflicts with evidence that fatty acids and glucose compete as metabolic substrates.

    “This concept conflicts with compelling evidence that fatty acids and glucose compete as metabolic substrates [74].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Randle, 1998, Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years, Diabetes Metab. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These mitochondrial traits are most often seen with aging, severe obesity, and type 2 diabetes, but also occur in young insulin-resistant offspring of diabetic parents.

    “These traits are most often observed in association with aging, severe obesity and type 2 diabetes but were also evident in young insulin-resistant offspring of parents with diabetes [60,62].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Morino, 2006, Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction, Diabetes source

      Not checked in the free run.

    • cites [62] Muoio, 2006, Obesity-related derangements in metabolic regulation, Annu. Rev. Biochem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Even-chain fatty acid-derived acylcarnitine intermediates are elevated in muscle of obese rodents and decrease after a two-week exercise intervention that restores glucose tolerance.

    “Several of the even chain, fatty acid-derived acylcarnitine intermediates were elevated in muscle of obese rodents, but decreased after a 2-week exercise intervention that restored glucose tolerance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Koves, 2005, Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-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 S4 (based).

    Premisenone given

    Skeletal muscle contains a large mitochondrial reserve that allows exponential increases in energy output during vigorous activity.

    “skeletal muscles harbor enormous mitochondrial reserve, enabling exponential increases in energy output during vigorous physical activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Greater mitochondrial mass should improve fat oxidation during moderate-to-high-intensity exercise but should have little effect at rest.

    “Expanded mitochondrial mass therefore affords the advantage of enhanced fat oxidation during moderate to high intensity exercise but should not have much impact at rest.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    Incomplete fat oxidation occurs when β-oxidation carbon flux exceeds acetyl-CoA entry into the TCA cycle.

    “which occurs when carbon flux through the β-oxidation machinery outpaces entry of acetyl-CoA (the final product of β-oxidation) into the TCA cycle.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The mitochondrial dysfunction theory implies that mitochondrial content or capacity determines resting fat oxidation rates.

    “the mitochondrial dysfunction theory of insulin resistance implies that mitochondrial content and/or capacity dictates resting rates of fat oxidation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Feeding rats a diet enriched with fat and branched-chain amino acids causes insulin resistance together with elevated intramuscular even- and odd-chain acylcarnitines.

    “feeding rats a diet enriched with both fat and branched chain amino acids caused insulin resistance in association with elevated intramuscular levels of both even and odd chain acylcarnitine metabolites [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Newgard, 2009, A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nur77 ablation increases susceptibility to diet-induced obesity and insulin resistance along with elevated intramuscular triacylglycerol and even-chain acylcarnitines.

    “genetic ablation of Nur77, a transcriptional regulator of glucose utilization genes in skeletal muscle, increased susceptibility to diet-induced obesity and insulin resistance in parallel with elevated IMTG content and accumulation of even-chained acylcarnitine species [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Chao, 2009, Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Insulin-resistant states are marked by increased whole-body fat oxidation, impaired switching to carbohydrate during the fasted-to-fed transition, and reduced muscle TCA cycle intermediates.

    “insulin resistant states were marked by increased whole body fat oxidation, impaired switching to carbohydrate substrate during the fasted to fed transition, and coincident reductions in muscle levels of several TCA cycle intermediates [50].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Koves, 2008, Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle-specific deletion of apoptosis inducing factor produces a phenotype similar to TFAM knockout, with reduced oxidative capacity and preserved insulin sensitivity.

    “A similar phenotype was reported as a consequence of muscle-specific deletion of apoptosis inducing factor (AIF), a protein that plays a key role in regulating the ETS [70].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Pospisilik, 2007, Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes, Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    A moderate-to-severe mitochondrial function deficit increases reliance on glycolytic metabolism, so genetic models with such deficits may adapt to enhance glucose uptake and insulin sensitivity.

    “Considering that a moderate to severe deficit in mitochondrial function increases reliance on glycolytic metabolism, it is not so surprising that these genetic maneuvers elicited adaptations that enhance glucose uptake and insulin sensitivity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Emerging reports argue against mitochondrial dysfunction as a root cause of muscle insulin resistance.

    “Although emerging reports appear to argue against a role for mitochondrial dysfunction as a root cause of muscle insulin resistance, the controversy might come down to a matter of definition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Lowering MCD activity in primary human skeletal myocytes with small interfering RNAs shifts metabolism from fatty acid to glucose oxidation and increases basal and insulin-stimulated glucose uptake.

    “lowering of MCD activity in primary human skeletal myocytes using small interfering RNAs invoked a clear shift from fatty acid to glucose oxidation and a corresponding increase in both basal and insulinstimulated glucose uptake [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Bouzakri, 2008, Malonyl coenzyme A decarboxylase regulates lipid and glucose metabolism in human skeletal muscle, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Unlike diabetic humans, AIF-null mice maintain insulin sensitivity and resist high-fat-diet-induced diabetes.

    “in contrast to the diabetic subjects, AIF null mice maintained insulin sensitivity and resisted the diabetogenic effects of a high fat diet.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Pospisilik, 2007, Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mcd−/− mice have decreased muscle acylcarnitine accumulation, enhanced glucose oxidation, and resistance to diet-induced glucose intolerance despite high intramuscular triacylglycerol and long-chain acyl-CoA levels.

    “the mcd−/− mice had decreased acylcarnitine accumulation in muscle, enhanced rates of glucose oxidation, and resisted diet-induced glucose intolerance, despite high intramuscular levels of triacylglycerol and long chain acyl-CoAs [50,88].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] 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 [88] Ussher, 2009, Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice lacking TFAM have reduced oxidative capacity but increased whole-body glucose tolerance and enhanced insulin-stimulated glucose uptake in isolated muscles.

    “mice lacking the mitochondrial transcription factor A (TFAM) have reduced oxidative capacity but increased whole body glucose tolerance and enhanced insulin-stimulated glucose uptake in isolated muscles [95].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Wredenberg, 2006, Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance, Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    A broader interpretation of mitochondrial dysfunction includes disturbances in fuel selection, anaplerotic and cataplerotic carbon flux, redox balance, and ROS production without measurable respiratory defects.

    “a broader interpretation of mitochondrial dysfunction encompasses perturbations that do not necessarily compromise oxidative potential. Thus, disturbances in mitochondrial fuel selection, anaplerotic and cataplerotic carbon flux, redox balance and production of reactive oxygen species (ROS) can occur in the absence of measurable defects in respiratory capacity [4,12,65].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] 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.

    • cites [12] Boucher, 2004, Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue, J. Biol. Chem. source

      Not checked in the free run.

    • cites [65] Noland, 2009, Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The increased glucose uptake after MCD inactivation is associated with higher cell-surface GLUT-4 but not with enhanced IRS-1 tyrosine phosphorylation, PI3-kinase activity, or Akt serine phosphorylation.

    “These outcomes were associated with increased cell surface levels of the GLUT-4 glucose transporter, but surprisingly no enhancement in insulin signaling at the levels of IRS-1 tyrosine phosphorylation, PI3-kinase activity, or serine phosphorylation of Akt.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Bouzakri, 2008, Malonyl coenzyme A decarboxylase regulates lipid and glucose metabolism in human skeletal muscle, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Whole-body or muscle-specific TXNIP deletion impairs oxidative muscle metabolism while producing mice that are highly insulin responsive even after high-fat feeding.

    “whole body or muscle-specific deletion of the redox regulatory protein, thioredoxin interaction protein (TXNIP), resulted in impaired oxidative muscle metabolism while also producing mice that were exquisitely insulin responsive, even after high fat feeding [38].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Hui, 2008, Txnip balances metabolic and growth signaling via PTEN disulfide reduction, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    A surplus of glucose and lipid fuel should raise mitochondrial membrane potential.

    “Thus, in theory, a surplus of both glucose and lipid fuel should raise mitochondrial membrane potential.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Persistently high fat oxidation may create a mitochondrial environment that favors ROS production.

    “persistently high rates of fat oxidation might foster a mitochondrial microenvironment that is conducive to ROS production.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    When energy delivery is high and ATP consumption is low, a high ATP/ADP ratio reduces proton flux through ATP synthase and slows electron transport.

    “When energy delivery is high (overfeeding) but ATP consumption is low (physical inactivity), a high ATP/ADP ratio reduces proton flux through ATP synthase and slows electron transport through the ETS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    These conditions increase mitochondrial membrane potential and the NADH/NAD ratio, which inhibits several TCA cycle enzymes.

    “These conditions increase mitochondrial membrane potential and the local ratio of NADH/NAD, which in turn imposes negative pressure on several TCA cycle enzymes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Insulin-resistant states in rodents and humans are associated with increased mitochondrial H2O2 emission potential and decreased skeletal muscle glutathione.

    “In both rodents and humans insulin resistant states were associated with increased mitochondrial H2O2 emission potential and decreased skeletal muscle levels of glutathione, a commonly used biomarker of oxidative/reductive stress due to its important role in detoxifying H2O2 [4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] 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

    Patients with inborn errors of metabolism present with nonketotic hypoglycemia, muscle weakness, elevated long-chain acylcarnitines, and systemic carnitine depletion.

    “Patients afflicted with these disorders present with nonketotic hypoglycemia, muscle weakness, pronounced elevations in long chain acylcarnitines and systemic carnitine depletion [91].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Wanders, 1999, Disorders of mitochondrial fatty acyl-CoA beta-oxidation, J. Inherit. Metab. Dis. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Exercise-induced mitochondrial adaptations and fiber type switching improve fitness and athletic performance, but their roles in combating obesity and diabetes remain based on circumstantial evidence.

    “Clearly, exercise-induced mitochondrial adaptations and fiber type switching contribute to improved fitness and athletic performance; however, their presumed roles in combating obesity and diabetes are still based on circumstantial evidence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both MCK-PPARα and MCK-PGC-1α transgenic mice have increased mitochondrial protein expression and enhanced fat oxidation capacity, yet are more susceptible to whole-body and skeletal muscle insulin resistance.

    “Both of these transgenic mouse models had increased expression of multiple mitochondrial proteins, leading to enhanced capacity for fat oxidation, but contrary to the predicted outcome they were more susceptible to whole body and skeletal muscle insulin resistance.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Choi, 2008, Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

    • cites [24] Finck, 2005, A potential link between muscle peroxisome proliferator-activated receptor-a signaling and obesity-related diabetes, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aerobic exercise training causes mitochondrial biogenesis and enhanced oxidative capacity, which coincide with insulin sensitization.

    “Much attention has centered on mitochondrial biogenesis and concomitant enhancement of oxidative capacity, both of which represent hallmark adaptations that occur in response to aerobic exercise training and coincide with insulin sensitization [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Holloszy, 1984, Adaptations of skeletal muscle to endurance exercise and their metabolic consequences, J. Appl. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The obesity-related decline in free carnitine is associated with increased whole-body fat oxidation, muscle long-chain acylcarnitine accumulation, decreased short-chain acylcarnitines, and impaired mitochondrial substrate switching from fatty acid to pyruvate.

    “The obesity-related decline in free carnitine was associated with increased whole body fat oxidation, muscle accumulation of long chain acylcarnitines, a corresponding decline in short chain acylcarnitine species, and impaired substrate switching from fatty acid to pyruvate when measured in isolated mitochondria.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Noland, 2009, Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acetylcarnitine is produced from acetyl-CoA by CrAT, which converts short-chain CoA species to acylcarnitines and regenerates free CoA.

    “This metabolite derives from acetyl-CoA via the action of carnitine acetyltransferase (CrAT), a mitochondrial enzyme that converts short chain CoA species to their acylcarnitine counterparts while also regenerating free CoA [21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Cordente, 2004, Redesign of carnitine acetyltransferase specificity by protein engineering, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Carnitine therapy improves glucose tolerance and insulin responsiveness in rodent models of aging, genetic diabetes, and high-fat feeding, and reverses obesity-related mitochondrial fuel-selection defects.

    “carnitine therapy improved glucose tolerance and insulin responsiveness in rodent models of aging, genetic diabetes and high fat feeding [65,71], while also reversing obesity-related derangements in mitochondrial fuel selection [65].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] Noland, 2009, Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control, J. Biol. Chem. source

      Not checked in the free run.

    • cites [71] Power, 2007, Carnitine revisited: potential use as adjunctive treatment in diabetes, Diabetologia source

      Not checked in the free run.

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

    Premisecitation

    l-carnitine is FDA-approved for inborn errors of metabolism.

    “l-carnitine is an FDA-approved therapy for inborn errors in metabolism [56].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Longo, 2006, Disorders of carnitine transport and the carnitine cycle, Am. J. Med. Genet. C. Semin. Med. Genet. source

      Not checked in the free run.

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

    Premisenone given

    Physical activity has well-recognized beneficial effects on insulin sensitivity and metabolic health.

    “The salutary impact of physical activity on insulin sensitivity, and metabolic health in general, has been well recognized for decades.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The MCK-PGC1α transgene increases mitochondrial content in type II fibers 2.4-fold without affecting type I fibers.

    “The MCK-PGC1α transgene caused a 2.4-fold increase in mitochondrial content of type II fibers without affecting type I fibers [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Choi, 2008, Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In MCK-PPARα mice, oxfenicine, a β-oxidation inhibitor, improves glucose tolerance, suggesting excessive fat oxidation contributes to the diabetic phenotype.

    “In the MCK-PPARα mice, administration of oxfenicine, a pharmacological inhibitor of β-oxidation, improved glucose tolerance, suggesting excessive fat oxidation contributed to the diabetic phenotype [24].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Finck, 2005, A potential link between muscle peroxisome proliferator-activated receptor-a signaling and obesity-related diabetes, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The increased oxidative power in MCK-PGC1α mice improves exercise performance versus wild-type but does not alter fat mass, total energy expenditure, or weight gain on a high-fat diet.

    “The resulting boost in oxidative power enabled superior exercise performance relative to wild-type mice [15] but did not change fat mass, total body energy expenditure or weight gain during a high fat diet.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Calvo, 2008, Muscle-specific expression of PPARgamma coactivator-1alpha improves exercise performance and increases peak oxygen uptake, J. Appl. Physiol. source

      Not checked in the free run.

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

    Interpretationreasoning

    An alternative explanation for the insulin-resistant phenotype of MCK-PGC1α mice is that increased intramuscular triacylglycerol and mitochondrial content promote preferential lipid oxidation, which antagonizes glucose uptake and utilization as predicted by the Randle hypothesis.

    “Equally plausible however, the combined increases in IMTG and mitochondrial content may have encouraged preferential oxidation of lipid substrate, thereby antagonizing the drive for glucose uptake and utilization as predicted by the Randle hypothesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both short-term and long-term exercise raise muscle levels of glycerolipid biosynthetic enzymes, along with greater IMTG synthesis and content.

    “Both acute and chronic exercise induce muscle expression of glycerolipid biosynthetic enzymes, which is coupled to increased IMTG synthesis and content [42,80].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Ikeda, 2002, Up-regulation of SREBP-1c and lipogenic genes in skeletal muscles after exercise training, Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

    • cites [80] 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.

  • May combine two claims.

    Premisecitation

    Mice overexpressing DGAT1 in muscle also showed mitochondrial abnormalities: altered morphology, 45% less mtDNA, and higher mRNA for CPT1 and uncoupling protein 3.

    “Interestingly however, DGAT1 overexpression was also accompanied by a complex set of mitochondrial abnormalities, including altered morphology, a 45% reduction in mtDNA and increased mRNA expression of metabolic genes such as CPT1 and uncoupling protein 3 [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Liu, 2009, Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1, Diabetes source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Storing fatty acid as IMTG may protect it from less desirable metabolic fates.

    “The study implies that sequestration of fatty acid into IMTG guards against less desirable fates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In humans, one exercise session improved insulin sensitivity alongside higher IMTG and lower muscle DAG, ceramide, and glycogen, measured the next day after lipid perfusion.

    “A recent study in humans showed that the insulin sensitizing properties of a single exercise session corresponded with elevated IMTG content and lower muscle levels of DAG, ceramide and muscle glycogen, all measured the day after exercise and following a lipid perfusion [80].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] 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.

  • May combine two claims.

    Interpretationreasoning

    Better insulin action was strongly linked to greater mitochondrial activity, but the leading candidate mediators of insulin resistance did not fall correspondingly.

    “Thus, these findings revealed a strong association between improved insulin action and enhanced mitochondrial activity, but without corresponding reductions in leading candidate mediators of insulin resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the Thyfault et al. study, levels of diacylglycerol, monoacylglycerol, and long chain acyl-CoAs did not fall and sometimes rose after contraction.

    “In line with this scenario, contraction caused a robust reduction in IMTG content of the obese muscles; however, diacylglycerol, monoacylglycerol and long chain acyl-CoAs were either unchanged or increased.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Thyfault, 2007, Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism, Am. J. Physiol. Cell Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that human one-legged exercise study, glycogen levels decreased but IMTG levels did not change.

    “In this investigation the experimental protocol resulted in decreased glycogen levels but did not affect IMTG levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Frosig, 2009, Reduced malonyl-CoA content in recovery from exercise correlates with improved insulin-stimulated glucose uptake in human skeletal muscle, Am. J. Physiol. Endocrinol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In lean and obese Zucker rats, contraction increased β-oxidation and mitochondrial carbon flux and reduced malonyl-CoA.

    “Analysis of mitochondrial-derived acylcarnitines showed that the contraction regimen elicited marked increases in β-oxidation and mitochondrial carbon flux, in parallel with reduced malonyl-CoA levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Thyfault, 2007, Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism, Am. J. Physiol. Cell Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Thyfault et al. study, obese rat muscle appeared to have greater fatty acid supply and mitochondrial use than lean rat muscle, with similar glycogen depletion.

    “Both the endogenous supply and mitochondrial use of fatty acid substrate appeared to be greater in muscle from the obese versus lean rats, despite similar rates of glycogen depletion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Thyfault, 2007, Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism, Am. J. Physiol. Cell Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In these mice, the outcomes accompany greater lipid droplet buildup, lower DAG and ceramide, and suppressed fatty acid oxidation and oxidative gene expression.

    “Deficiency of ATGL in whole body knockout mice results in severe metabolic disruptions, cardiac dysfunction and premature death [29], which occurs in association with increased tissue lipid droplet accumulation, decreased DAG and ceramide levels, and inhibition of both fatty acid oxidation and mRNA expression of oxidative genes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Haemmerle, 2006, Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Whole-body ATGL knockout mice exhibit severe metabolic disruptions, cardiac dysfunction, and premature death.

    “Deficiency of ATGL in whole body knockout mice results in severe metabolic disruptions, cardiac dysfunction and premature death [29], which occurs in association with increased tissue lipid droplet accumulation, decreased DAG and ceramide levels, and inhibition of both fatty acid oxidation and mRNA expression of oxidative genes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Haemmerle, 2006, Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase, Science source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Animal models allow proof-of-concept experiments that would be hard or impossible in humans.

    “Still, the animal models permit proof-of-concept experiments that are difficult, or even impossible, to accomplish in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    These mice also show greater glucose use, lower liver and muscle glycogen, and improved whole-body and skeletal muscle insulin sensitivity.

    “As a result, these mice exhibit increased glucose use, depleted liver and muscle glycogen levels, and enhanced whole body and skeletal muscle insulin sensitivity [29,39,48].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Haemmerle, 2006, Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase, Science source

      Not checked in the free run.

    • cites [39] Huijsman, 2009, Adipose triacylglycerol lipase deletion alters whole body energy metabolism and impairs exercise performance in mice, Am. J. Physiol. Endocrinol. Metab. source

      Not checked in the free run.

    • cites [48] Kienesberger, 2009, Adipose triglyceride lipase deficiency causes tissue-specific changes in insulin signaling, J. Biol. Chem. source

      Not checked in the free run.

57 of 57

  • The paper relies on this without support.

    At least part of the health benefit of routine physical activity comes from redistribution of body fat and adjustments in whole-body lipid balance.

    “It is also likely that at least some of this benefit is secondary to redistribution of body fat and adjustments in whole body lipid balance.”

  • The paper relies on this without support.

    Few studies have directly examined contraction-induced reversal of insulin resistance alongside global changes in muscle lipid metabolites.

    “However, few studies have directly examined contraction-induced reversal of insulin resistance in accord with global changes in muscle lipid metabolites.”

  • The paper relies on this without support.

    Muscle contraction increases mitochondrial flux and degradation of carbon substrates, including fatty acids.

    “Clearly, muscle contraction increases mitochondrial flux and degradation of carbon substrates, including but not limited to fatty acids.”
3 of 3

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?

  • Transgenic mouse models with targeted disruptions in mitochondrial proteins or master regulators of mitochondrial biogenesis have severely compromised oxidative performance, but many show increased insulin sensitivity relative to wild type, even on a fat-enriched diet.

    “As anticipated these mice have severely compromised oxidative performance, but contrary to the predicted development of insulin resistance, many of these transgenic models display increased insulin sensitivity relative to wild type mice, even when challenged with a fat-enriched diet (reviewed in (Muoio, 2010)).”

    From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Muoio, 2010

  • Fatty acid oxidation intermediates may also create an unfavorable environment in the mitochondria, which contributes to the formation of ROS and the development of oxidative stress.

    “FAO intermediates may also create an unfavorable environment in the mitochondria, which contributes to the formation of ROS and the development of oxidative stress ([119](#B119), [120](#B120)).”

    From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [119]

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. Longo, 2006, Disorders of carnitine transport and the carnitine cycle, Am. J. Med. Genet. C. Semin. Med. Genet., 142C, 77, 10.1002/ajmg.c.30087 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Muoio, D. M.
Affiliations
Duke University (US)
Corresponding author
Muoio, Deborah M.
ORCID
Muoio, Deborah M.
Venue
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Publisher
Elsevier BV
Published
2010-03
Volume
1801
Issue
3
Pages
281-288
ISSN
1388-1981 (ISSN-L)
DOI
10.1016/j.bbalip.2009.11.007
PMC
PMC4428562
OpenAlex
W2055517980
Cited by
137
References
97
Citations by year
2025: 3 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 8 · 2020: 2 · 2019: 4 · 2018: 8 · 2017: 7 · 2016: 13 · 2015: 11 · 2014: 9 · 2013: 15 · 2012: 21
FWCI
1.17
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Diabetes Association
  • National Institutes of Health
  • National Institute on Aging (R01AG028930, P30AG028716)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056112, K01-DK56112, K01DK067200, R01DK089312)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
insulin resistance, lipotoxicity, skeletal muscle, lipid oxidation, physical activity, ceramide, diacylglycerol, serine kinase, insulin signaling, lipid metabolism
MeSH terms
Animals, Carnitine, Disease Models, Animal, Humans, Insulin Resistance, Triglycerides, Lipid Peroxidation, Exercise, Muscle, Skeletal, Mitochondrial Diseases, Lipid Metabolism

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 ›

Are you an author, or do you see a problem with this page? Request a review