ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity
Open accessAbstract
AIMS/HYPOTHESIS: Dissipating energy via mitochondrial uncoupling has been suggested to contribute to enhanced insulin sensitivity. We hypothesised that skeletal muscle mitochondria of endurance-trained athletes have increased sensitivity for fatty acid (FA)-induced uncoupling, which is driven by the mitochondrial protein adenine nucleotide translocase 1 (ANT1). METHODS: Capacity for FA-induced uncoupling was measured in endurance-trained male athletes (T) and sedentary young men (UT) in an observational study and also in isolated skeletal muscle mitochondria from Zucker diabetic fatty (ZDF) rats and C2C12 myotubes following small interfering RNA (siRNA)-mediated gene silencing of ANT1. Thus, fuelled by glutamate/succinate (fibres) or pyruvate (mitochondria and myotubes) and in the presence of oligomycin to block ATP synthesis, increasing levels of oleate (fibres) or palmitate (mitochondria and myotubes) were automatically titrated while respiration was monitored. Insulin sensitivity was measured by hyperinsulinaemic-euglycaemic clamp in humans and via insulin-stimulated glucose uptake in myotubes. RESULTS: Skeletal muscle from the T group displayed increased sensitivity to FA-induced uncoupling (p = 0.011) compared with muscle from the UT group, and this was associated with elevated insulin sensitivity (p = 0.034). ANT1 expression was increased in T (p = 0.013). Mitochondria from ZDF rats displayed decreased sensitivity for FA-induced uncoupling (p = 0.008). This difference disappeared in the presence of the adenine nucleotide translocator inhibitor carboxyatractyloside. Partial knockdown of ANT1 in C2C12 myotubes decreased sensitivity to the FA-induced uncoupling (p = 0.008) and insulin-stimulated glucose uptake (p = 0.025) compared with controls. CONCLUSIONS/INTERPRETATION: Increased sensitivity to FA-induced uncoupling is associated with enhanced insulin sensitivity and is affected by ANT1 activity in skeletal muscle. FA-induced mitochondrial uncoupling may help to preserve insulin sensitivity in the face of a high supply of FAs. TRIAL REGISTRATION: www.trialregister.nl NTR2002.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
The molecular mechanism of ANT uncoupling is suggested to depend on transport of fatty acids.
“The molecular mechanism is not entirely clear but has been suggested to depend on the transport of fatty acids [23,24].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [24]
ANT-1 can mediate fatty acid-induced uncoupling via its ability to transfer fatty acid anions across the inner mitochondrial membrane, in addition to catalysing exchange of cytoplasmic ADP for mitochondrial ATP.
“in addition to catalysing the exchange of cytoplasmic ADP for mitochondrial ATP, ANT-1 can mediate fatty acid-induced uncoupling via its ability to transfer fatty acid anions across the inner mitochondrial membrane [63].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [63]
Partial silencing of ANT-1 in cultured C2C12 myotubes results in reduced cellular sensitivity to fatty acid-induced uncoupling and a significant reduction in insulin-stimulated glucose uptake.
“studies in cultured C2C12 myotubes, in which partial silencing of ANT-1 results in reduced cellular sensitivity to fatty acid-induced uncoupling and a significant reduction in insulin-stimulated glucose uptake [63].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [63]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Glucose clamp technique: a method for quantifying insulin secretion and resistance.
DeFronzo, R. A., Tobin, J. D., & Andres, R. (1979) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1979.237.3.e214 · Cited by 7,425 · see citing works
Brown Adipose Tissue: Function and Physiological Significance
CANNON, B., & NEDERGAARD, J. (2004) · Physiological Reviews · doi:10.1152/physrev.00015.2003 · Cited by 6,433 · see citing works
Udenfriend, S., Stein, S., Böhlen, P., Dairman, W. M., Leimgruber, W., & Weigele, M. (1972) · Science · doi:10.1126/science.178.4063.871 · Cited by 2,639 · see citing works
Reactive oxygen species have a causal role in multiple forms of insulin resistance
Houstis, N., Rosen, E. D., & Lander, E. S. (2006) · Nature · doi:10.1038/nature04634 · Cited by 2,525 · see citing works
Chomczyński, P., & Sacchi, N. (2006) · Nature Protocols · doi:10.1038/nprot.2006.83 · Cited by 2,084 · see citing works
Anderson, E. J., Lustig, M. E., Boyle, K. E., Woodlief, T. L., Kane, D. A., Lin, C.-T., Price, J. W., Kang, L., Rabinovitch, P. S., Szeto, H. H., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37048 · Cited by 1,253 · see citing works
Goodpaster, B. H. (2001) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.12.5755 · Cited by 1,194 · see citing works
Percutaneous Needle Biopsy of Skeletal Muscle in Physiological and Clinical Research
Bergström, J. P. (1975) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.3109/00365517509095787 · Cited by 1,159 · see citing works
Sparks, L. M., Xie, H., Koza, R. A., Mynatt, R., Hulver, M. W., Bray, G. A., & Smith, S. R. (2005) · Diabetes · doi:10.2337/diabetes.54.7.1926 · Cited by 629 · cited 1× · see citing works
“Real-time quantitative RT-PCR (qRT-PCR) reactions were performed as one-step reactions on the ABI PRISM 7900 realtime PCR system fromApplied Biosystems (Nieuwerkerk aan den Ijssel, the Netherlands) as previously described [28].”
MethodSelf-citationSarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals
Bal, N. C., Maurya, S. K., Sopariwala, D. H., Sahoo, S. K., Gupta, S. C., Shaikh, S. A., Pant, M., Rowland, L. A., Bombardier, É., Goonasekera, S. A., et al. (2012) · Nature Medicine · doi:10.1038/nm.2897 · Cited by 553 · see citing works
Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation
Skulachev, V. P. (1991) · FEBS Letters · doi:10.1016/0014-5793(91)80658-p · Cited by 467 · see citing works
The basal proton conductance of mitochondria depends on adenine nucleotide translocase content
Brand, M. D., Pakay, J. L., Ocloo, A., Kokoszka, J., Wallace, D. C., Brookes, P. S., & Cornwall, E. J. (2005) · Biochemical Journal · doi:10.1042/bj20050890 · Cited by 410 · see citing works
Richieri, G. V., Anel, A., & Kleinfeld, A. M. (1993) · Biochemistry · doi:10.1021/bi00080a032 · Cited by 368 · see citing works
Phielix, E., Schrauwen-Hinderling, V. B., Mensink, M., Lenaers, E., Meex, R., Hoeks, J., Kooi, M. E., Moonen-Kornips, E., Sels, J.-P., Hesselink, M. K. C., et al. (2008) · Diabetes · doi:10.2337/db08-0391 · Cited by 359 · see citing works
Self-citationMeex, R. C. R., Schrauwen-Hinderling, V. B., Moonen-Kornips, E., Schaart, G., Mensink, M., Phielix, E., van de Weijer, T., Sels, J.-P., Schrauwen, P., & Hesselink, M. K. C. (2010) · Diabetes · doi:10.2337/db09-1322 · Cited by 355 · see citing works
Self-citationThe ATP/ADP‐antiporter is involved in the uncoupling effect of fatty acids on mitochondria
Andreyev, A. Y., BONDAREVA, T. O., Dedukhova, V. I., MOKHOVA, E. N., Skulachev, V. P., TSOFINA, L. M., Волков, Н. И., & VYGODINA, T. V. (1989) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1989.tb14867.x · Cited by 302 · see citing works
Phielix, E., Meex, R., Moonen-Kornips, E., Hesselink, M. K. C., & Schrauwen, P. (2010) · Diabetologia · doi:10.1007/s00125-010-1764-2 · Cited by 206 · see citing works
Self-citationChoi, C. S., Fillmore, J. J., Kim, J. K., Liu, Z., Kim, S., Collier, E. F., Kulkarni, A. S., Distefano, A. G., Hwang, Y.-J., Kahn, M., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci13579 · Cited by 182 · see citing works
Lefort, N., Glancy, B., Bowen, B., Willis, W. T., Bailowitz, Z., De Filippis, E. A., Brophy, C., Meyer, C., Højlund, K., Yi, Z., et al. (2010) · Diabetes · doi:10.2337/db10-0174 · Cited by 174 · see citing works
Nielsen, J., Mogensen, M., Vind, B. F., Sahlin, K., Højlund, K., Schrøder, H. D., & Ørtenblad, N. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00692.2009 · Cited by 158 · see citing works
Hoeks, J., van Herpen, N. A., Mensink, M., Moonen-Kornips, E., van Beurden, D., Hesselink, M. K. C., & Schrauwen, P. (2010) · Diabetes · doi:10.2337/db10-0519 · Cited by 156 · see citing works
Self-citationDécombaz, J., Schmitt, B., Ith, M., Decarli, B., Diem, P., Kreis, R., Hoppeler, H. H., & Boesch, C. (2001) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.281.3.r760 · Cited by 154 · see citing works
Effects of acute and chronic endurance exercise on mitochondrial uncoupling in human skeletal muscle
Fernström, M., Tonkonogi, M., & Sahlin, K. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.055202 · Cited by 148 · see citing works
Befroy, D. E., Petersen, K. F., Dufour, S., Mason, G. F., Rothman, D. L., & Shulman, G. I. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808889105 · Cited by 118 · see citing works
Taddeo, E. P., Laker, R. C., Breen, D. S., Akhtar, Y., Kenwood, B. M., Liao, J. A., Zhang, M., Fazakerley, D. J., Tomsig, J. L., Harris, T. E., et al. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2013.11.003 · Cited by 116 · see citing works
Respiratory Uncoupling in Skeletal Muscle Delays Death and Diminishes Age-Related Disease
Gates, A. C., Bernal‐Mizrachi, C., Chinault, S. L., Chu, F., Schneider, J. G., Coleman, T., Malone, J. P., Townsend, R. R., Chakravarthy, M. V., & Semenkovich, C. F. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.010 · Cited by 113 · see citing works
Shabalina, I. G., Joris Hoeks, J., Kramarova, T. V., Schrauwen, P., Cannon, B., & Nedergaard, J. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.02.033 · Cited by 101 · see citing works
Self-citationHigh Oxidative Capacity Due to Chronic Exercise Training Attenuates Lipid-Induced Insulin Resistance
Phielix, E., Meex, R., Ouwens, D. M., Sparks, L., Hoeks, J., Schaart, G., Moonen-Kornips, E., Hesselink, M. K. C., & Schrauwen, P. (2012) · Diabetes · doi:10.2337/db11-1832 · Cited by 99 · cited 6× · see citing works
“Data on lipid-induced insulin sensitivity was published previously [4].”
BackgroundMethodResultInfluentialSelf-citationProtein expression of UCP3 differs between human type 1, type 2a, and type 2b fibers
Hesselink, M. K. C., KEIZER, H. A., Borghouts, L. B., Schaart, G., Kornips, C. F. P., Slieker, L. J., Sloop, K. W., Saris, W. H. M., & Schrauwen, P. (2001) · The FASEB Journal · doi:10.1096/fj.00-0517fje · Cited by 87 · see citing works
Self-citationNabben, M., Joris Hoeks, J., Briedé, J. J., Glatz, J. F. C., Moonen‐Kornips, E., Hesselink, M. K. C., & Schrauwen, P. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.11.016 · Cited by 84 · see citing works
Self-citationRussell, A. P., Wadley, G. D., Hesselink, M. K. C., Schaart, G., Lo, S. K., Léger, B., GARNHAM, A. P., Moonen‐Kornips, E., Cameron‐Smith, D., Giacobino, J., et al. (2003) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-002-0943-5 · Cited by 72 · see citing works
Self-citationDaubas, P., Klarsfeld, A., Garner, I., Pinset, C., Cox, R., & BUCKINGHAM, M. E. (1988) · Nucleic Acids Research · doi:10.1093/nar/16.4.1251 · Cited by 70 · see citing works
Hoeks, J., Briedé, J. J., de Vogel, J., Schaart, G., Nabben, M., Moonen-Kornips, E., Hesselink, M. K. C., & Schrauwen, P. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.01.013 · Cited by 63 · see citing works
Self-citationRemodeling Lipid Metabolism and Improving Insulin Responsiveness in Human Primary Myotubes
Sparks, L. M., Moro, C., Ukropcová, B., Bajpeyi, S., Civitarese, A. E., Hulver, M. W., Thoresen, G. H., Rustan, A. C., & Smith, S. R. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021068 · Cited by 61 · see citing works
Self-citationMielke, C., Lefort, N., McLean, C. G., Cordova, J. M., Langlais, P. R., Bordner, A. J., Te, J. A., Ozkan, S. B., Willis, W. T., & Mandarino, L. J. (2014) · Biochemistry · doi:10.1021/bi401651e · Cited by 53 · see citing works
Chavez, A. O., Kamath, S., Jani, R., Sharma, L. K., Monroy, A., Abdul-Ghani, M. A., Centonze, V. E., Sathyanarayana, P., Coletta, D. K., Jenkinson, C. P., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1387 · Cited by 52 · see citing works
Paglialunga, S., van Bree, B., Bosma, M., Valdecantos, M. P., Amengual-Cladera, E., Jörgensen, J. A., van Beurden, D., den Hartog, G. J. M., Ouwens, D. M., Briedé, J. J., et al. (2012) · Diabetologia · doi:10.1007/s00125-012-2626-x · Cited by 45 · see citing works
Self-citationNabben, M., Shabalina, I. G., Moonen‐Kornips, E., van Beurden, D., Cannon, B., Schrauwen, P., Nedergaard, J., & Joris Hoeks, J. (2011) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2011.04.003 · Cited by 39 · see citing works
Self-citationPalmitate-induced skeletal muscle insulin resistance does not require NF-κB activation
Hommelberg, P. P. H., Plat, J., Sparks, L. M., Schols, A. M. W. J., van Essen, A. L. M., KELDERS, M. C. J. M., van Beurden, D., Mensink, R. P., & LANGEN, R. C. J. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0515-3 · Cited by 27 · see citing works
Self-citationEliminating the Ant1 Isoform Produces a Mouse with CPEO Pathology but Normal Ocular Motility
Yin, H., Stahl, J. S., Andrade, F. H., McMullen, C. A., Webb-Wood, S., Newman, N. J., Biousse, V., Wallace, D. C., & Pardue, M. T. (2005) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.05-0695 · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases
Demine, S., Renard, P., & Arnould, T. (2019) · Cells · doi:10.3390/cells8080795 · Cited by 476 · see citing works
“The molecular mechanism is not entirely clear but has been suggested to depend on the transport of fatty acids [23,24].”
BackgroundSkeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus
Hesselink, M. K. C., Schrauwen-Hinderling, V., & Schrauwen, P. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.104 · Cited by 242 · see citing works
Self-citationProtein assemblies ejected directly from native membranes yield complexes for mass spectrometry
Chorev, D. S., Baker, L. A., Wu, D., Beilsten-Edmands, V., Rouse, S. L., Zeev-Ben-Mordehai, T., Jiko, C., Samsudin, F., Gerle, C., Khalid, S., et al. (2018) · Science · doi:10.1126/science.aau0976 · Cited by 191 · see citing works
Nisr, R. B., Shah, D. S., Ganley, I. G., & Hundal, H. S. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03148-8 · Cited by 142 · see citing works
The manifold role of the mitochondria in skeletal muscle insulin resistance
Cade, W. T. (2018) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000480 · Cited by 21 · see citing works
- Authors
- Sparks, L. M., Gemmink, A., Phielix, E., Bosma, M., Schaart, G., Moonen-Kornips, E., Jörgensen, J. A., Nascimento, E. B. M., Hesselink, M. K. C., Schrauwen, P., & Hoeks, J.
- Affiliations
- Maastricht University (NL)
- Karolinska Institutet (SE)
- ORCID
- Venue
- Diabetologia
- Published
- 2016-02-17
- Volume
- 59
- Issue
- 5
- Pages
- 1030-1039
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC4826430
- OpenAlex
- W2282815582
- Cited by
- 34
- References
- 40
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 5 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 2 · 2016: 3
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Diabetologia (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- Funders
- European Foundation for the Study of Diabetes
- Diabetes Fonds (2004.00.059)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (918.96.618)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- ANT1, mitochondrial uncoupling, insulin sensitivity, skeletal muscle mitochondria, endurance training, athletes, carboxyatractyloside, insulin-stimulated glucose uptake, fatty acids, type 2 diabetes, Zucker diabetic fatty rats, C2C12 myotubes, gene silencing
- MeSH terms
- Mitochondrial ADP, ATP Translocases, Animals, Fatty Acids, Humans, Insulin, Insulin Resistance, Male, Mitochondria, Muscle, Rats, Zucker, Muscle, Skeletal, Muscle Fibers, Skeletal, Oleic Acid, Palmitic Acid, Adenine Nucleotide Translocator 1, Rats, In Vitro Techniques
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.
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
