Short-term increase of plasma free fatty acids does not interfere with intrinsic mitochondrial function in healthy young men
Abstract
Free fatty acid (FFA)- and obesity-induced insulin resistance has been associated with disturbed mitochondrial function. Elevated plasma FFA can impair insulin-induced increase of adenosine triphosphate synthesis and downregulate the expression of genes important in the biogenesis of mitochondria in human skeletal muscle. Whether FAs have a direct effect on intrinsic mitochondrial capacity remains to be established. Therefore, we measured ex vivo mitochondrial respiratory capacity in human skeletal muscle after exposure to hyperinsulinemia and high levels of plasma FFA. Nine healthy lean men were studied during a 6-hour hyperinsulinemic (600 pmol/L) euglycemic clamp with concomitant infusion of Intralipid (Fresensius Kabi Nederland, Den Bosch, the Netherlands) (FFA clamped at 0.5 mmol/L) or saline. Mitochondrial respiratory capacity was measured by high-resolution respirometry in permeabilized muscle fibers using an Oxygraph (OROBOROS Instruments, Innsbruck, Austria). Each participant served as his own control. Peripheral glucose uptake (rate of disappearance) was significantly lower during infusion of the lipid emulsion compared with the control saline infusion (68 μmol/kg·min [saline] vs 40 μmol/kg·min [lipid], P = .008). However, adenosine diphosphate-stimulated and maximal carbonylcyanide-4-(trifluoromethoxy)-phenylhydrazone-stimulated uncoupled respiration rates were not different in permeabilized skeletal muscle fibers after exposure to high levels of FFA compared with the control condition. We conclude that short-term elevation of FFA within the physiological range induces insulin resistance but does not affect intrinsic mitochondrial capacity in skeletal muscle in humans.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Short-term lipid infusion for 6 to 8 h in healthy individuals does not change mitochondrial content, morphology, and respiration rates in skeletal muscle despite a lower mitochondrial membrane potential.
“Short-term lipid infusion for 6 to 8 h in healthy individuals does not change mitochondrial content, morphology, and respiration rates in skeletal muscle despite a lower mitochondrial membrane potential (4, 10).”
From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [4]
Cites
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus* (2002) · Diabetes Care · doi:10.2337/diacare.25.2007.s5 · Cited by 10,320 · see citing works
ATS/ACCP statement on cardiopulmonary exercise testing
(2003) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.167.2.211 · Cited by 3,026 · see citing works
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2003) · Diabetes Care · doi:10.2337/diacare.26.2007.s5 · Cited by 2,689 · see citing works
ATS/ACCP statement on cardiopulmonary exercise testing.
Ross, R. M. (2003) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.167.10.950 · Cited by 2,563 · see citing works
Calculation of substrate oxidation rates in vivo from gaseous exchange.
Frayn, K. N. (1983) · Journal of Applied Physiology · doi:10.1152/jappl.1983.55.2.628 · Cited by 2,365 · see citing works
Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes
Kelley, D. E., He, J., Menshikova, E. V., & Ritov, V. B. (2002) · Diabetes · doi:10.2337/diabetes.51.10.2944 · Cited by 2,321 · see citing works
Koves, T. R., Ussher, J. R., Noland, R. C., Slentz, D., Mosedale, M., Ilkayeva, O., Bain, J., Stevens, R., Dyck, J. R. B., Newgard, C. B., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.013 · Cited by 1,990 · see citing works
Topology of superoxide production from different sites in the mitochondrial electron transport chain
St-Pierre, J., Buckingham, J. A., Roebuck, S. J., & Brand, M. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207217200 · Cited by 1,545 · see citing works
Itani, S. I., Ruderman, N. B., Schmieder, F., & Boden, G. (2002) · Diabetes · doi:10.2337/diabetes.51.7.2005 · Cited by 1,390 · see citing works
Bonnard, C., Durand, A., Peyrol, S., Chanseaume, E., Chauvin, M.-A., Morio, B., Vidal, H., & Rieusset, J. (2008) · Journal of Clinical Investigation · doi:10.1172/jci32601 · Cited by 819 · see citing works
Regulatory role for the arginine–nitric oxide pathway in metabolism of energy substrates
Jobgen, W. S., Fried, S. K., Fu, W. J., Meininger, C. J., & Wu, G. (2006) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2005.12.001 · Cited by 713 · 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 2× · see citing works
“A 6-hour elevation of plasma FFA may be too short to induce detrimental changes on mitochondrial biogenesis and intrinsic capacity, as it has been shown that expression of genes that are involved in mitochondrial functioning does not alter over this short period [11,33], whereas prolonged exposure of 48 hours or 3-day…”
BackgroundMitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes
Mogensen, M., Sahlin, K., Fernström, M., Glintborg, D., Vind, B. F., Beck-Nielsen, H., & Højlund, K. (2007) · Diabetes · doi:10.2337/db06-0981 · Cited by 573 · see citing works
Finegood, D. T., Bergman, R. N., & Vranić, M. (1987) · Diabetes · doi:10.2337/diab.36.8.914 · Cited by 546 · see citing works
High-fat diets cause insulin resistance despite an increase in muscle mitochondria
Hancock, C. R., Han, D.-H., Chen, M., Terada, S., Yasuda, T., Wright, D. C., & Holloszy, J. O. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802057105 · Cited by 538 · see citing works
Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle
Boushel, R., Gnaiger, E., Schjerling, P., Skovbro, M., Kraunsøe, R., & Dela, F. (2007) · Diabetologia · doi:10.1007/s00125-007-0594-3 · Cited by 519 · see citing works
Effects of fat on insulin-stimulated carbohydrate metabolism in normal men.
Boden, G., Jadali, F., White, J. V., Liang, Y. T., Mozzoli, M. A., Chen, X., Coleman, E., & Smith, C. R. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115399 · Cited by 500 · see citing works
Stump, C. S., Short, K. R., Bigelow, M. L., Schimke, J. M., & Nair, K. S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1332551100 · Cited by 477 · see citing works
Capacity of oxidative phosphorylation in human skeletal muscle
Gnaiger, E. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.03.013 · Cited by 446 · see citing works
Oxidative Capacity, Lipotoxicity, and Mitochondrial Damage in Type 2 Diabetes
Schrauwen, P., & Hesselink, M. K. C. (2004) · Diabetes · doi:10.2337/diabetes.53.6.1412 · Cited by 408 · see citing works
Self-citationDose-Response Effect of Elevated Plasma Free Fatty Acid on Insulin Signaling
Belfort, R., Mandarino, L., Kashyap, S., Wirfel, K., Pratipanawatr, T., Berria, R., DeFronzo, R. A., & Cusi, K. (2005) · Diabetes · doi:10.2337/diabetes.54.6.1640 · Cited by 404 · see citing works
Bachmann, O. P., Dahl, D. B., Brechtel, K., Machann, J., Haap, M., Maier, T., Loviscach, M., Stumvoll, M., Claussen, C. D., Schick, F., et al. (2001) · Diabetes · doi:10.2337/diabetes.50.11.2579 · Cited by 369 · cited 2× · see citing works
“concentrations of different FA metabolites [42,43].”
BackgroundPhielix, 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-citationAbdominal Obesity: Role in the Pathophysiology of Metabolic Disease and Cardiovascular Risk
Bergman, R. N., Kim, S. P., Hsu, I. R., Catalano, K. J., Chiu, J. D., Kabir, M., Richey, J. M., & Ader, M. (2007) · The American Journal of Medicine · doi:10.1016/j.amjmed.2006.11.012 · Cited by 287 · see citing works
Richardson, D. K., Kashyap, S., Bajaj, M., Cusi, K., Mandarino, S. J., Finlayson, J., DeFronzo, R. A., Jenkinson, C. P., & Mandarino, L. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m408985200 · Cited by 259 · see citing works
Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle
Brehm, A., Krssak, M., Schmid, A. I., Nowotny, P., Waldhäusl, W., & Roden, M. (2006) · Diabetes · doi:10.2337/diabetes.55.01.06.db05-1286 · Cited by 239 · see citing works
Interaction between free fatty acids and glucose metabolism
Boden, G. H. (2002) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/00075197-200209000-00014 · Cited by 222 · see citing works
Toledo, F. G. S., Menshikova, E. V., Azuma, K., Radiková, Z., Kelley, C. A., Ritov, V. B., & Kelley, D. E. (2008) · Diabetes · doi:10.2337/db07-1429 · Cited by 218 · see citing works
Asmann, Y. W., Stump, C. S., Short, K. R., Coenen-Schimke, J. M., Guo, Z., Bigelow, M. L., & Nair, K. S. (2006) · Diabetes · doi:10.2337/db05-1230 · Cited by 207 · see citing works
Thematic review series: Patient-Oriented Research. Free fatty acid metabolism in human obesity
Koutsari, C., & Jensen, M. D. (2006) · Journal of Lipid Research · doi:10.1194/jlr.r600011-jlr200 · Cited by 198 · see citing works
Skeletal muscle “mitochondrial deficiency” does not mediate insulin resistance
Holloszy, J. O. (2009) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.26717c · Cited by 175 · see citing works
Manco, M., Greco, A., Capristo, E., Gniuli, D., Gaetano, A. D., & Gasbarrini, A. (2000) · Metabolism · doi:10.1016/s0026-0495(00)91377-5 · Cited by 168 · see citing works
Roden, M. (2005) · International Journal of Obesity · doi:10.1038/sj.ijo.0803102 · Cited by 149 · see citing works
Abdul-Ghani, M. A., Muller, F. L., Liu, Y., Chavez, A. O., Balas, B., Zuo, P., Chang, Z., Tripathy, D., Jani, R., Molina-Carrion, M., et al. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90287.2008 · Cited by 140 · see citing works
Ackermans, M. T., Arias, A. M. P., Bisschop, P. H. L. T., Endert, E., Sauerwein, H. P., & Romijn, J. A. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.5.7383 · Cited by 94 · see citing works
Self-citationMustelin, L., Pietiläinen, K. H., Rissanen, A., Sovijärvi, A. R., Piirilä, P., Naukkarinen, J., Peltonen, L., Kaprio, J., & Yki-Järvinen, H. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00580.2007 · Cited by 85 · see citing works
Ackermans, M. T. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.5.2220 · Cited by 84 · see citing works
Self-citationKhalfallah, Y., Fages, S., Laville, M., Langin, D., & Vidal, H. (2000) · Diabetes · doi:10.2337/diabetes.49.1.25 · Cited by 78 · see citing works
Hoeks, J., Hesselink, M. K. C., Russell, A. P., Mensink, M., Saris, W. H. M., Mensink, R. P., & Schrauwen, P. (2006) · Diabetologia · doi:10.1007/s00125-006-0369-2 · Cited by 74 · see citing works
Self-citationJarmuszkiewicz, W., Navet, R., Alberici, L. C., Douette, P., Sluse‐Goffart, C. M., Sluse, F. E., & Vercesi, A. E. (2004) · Journal of Bioenergetics and Biomembranes · doi:10.1023/b:jobb.0000047331.25248.7a · Cited by 58 · see citing works
Frederiksen, C. M., Højlund, K., Hansen, L., Oakeley, E. J., Hemmings, B., Abdallah, B. M., Brusgaard, K., Beck-Nielsen, H., & Gaster, M. (2008) · Diabetologia · doi:10.1007/s00125-008-1122-9 · Cited by 57 · see citing works
Dumas, J., Simard, G., Flamment, M., Ducluzeau, P., & Ritz, P. (2009) · Diabetes & Metabolism · doi:10.1016/j.diabet.2009.02.002 · Cited by 55 · see citing works
Chow, L. S., From, A. H. L., & Seaquist, E. R. (2009) · Metabolism · doi:10.1016/j.metabol.2009.07.009 · 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
Acute elevation of plasma lipids does not affect ATP synthesis in human skeletal muscle
Brehm, A., Krššák, M., Schmid, A. I., Nowotny, P., Waldhäusl, W. K., & Roden, M. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00756.2009 · Cited by 33 · see citing works
Clore, J. N., Stillman, J. S., Li, J., O’Keefe, S. J., & Levy, J. R. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00360.2003 · Cited by 28 · see citing works
Herlein, J. A., Fink, B. D., & Sivitz, W. I. (2009) · Metabolism · doi:10.1016/j.metabol.2009.07.021 · Cited by 25 · see citing works
Ogata (1997) · doi:10.1002/(sici)1097-0185(199706)248:2
Flagged first, then by citations
1 of the 49 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Jheng, H.-F., Tsai, P.-J., Guo, S.-M., Kuo, L.-H., Chang, C.-S., Su, I.-J., Chang, C.-R., & Tsai, Y.-S. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.05603-11 · Cited by 650 · see citing works
Interorgan Metabolic Crosstalk in Human Insulin Resistance
Gancheva, S., Jeleník, T., Álvarez-Hernández, E., & Roden, M. (2018) · Physiological Reviews · doi:10.1152/physrev.00015.2017 · Cited by 192 · see citing works
Excess of free fatty acids as a cause of metabolic dysfunction in skeletal muscle
TUMOVA, J., ANDEL, M., & TRNKA, J. (2016) · Physiological Research · doi:10.33549/physiolres.932993 · Cited by 143 · see citing works
“…humans, however, is incompatible with this concept and observed lipid-induced IR in skeletal muscle without an impairment of mitochondrial function (Brands et al. 2011, Hoeks et al. 2011, Fisher-Wellman et al. 2013) or with impairment which developed long time after the establishment of IR…”
BackgroundHe, S., Wang, S., Chen, X., Jiang, L., Peng, Y., Li, L., Wan, L., & Cui, K. (2011) · Metabolism · doi:10.1016/j.metabol.2011.05.007 · Cited by 106 · see citing works
Dubé, J. J., Coen, P. M., DiStefano, G., Chacon, A. C., Helbling, N. L., Desimone, M. E., Stafanovic-Racic, M., Hames, K. C., Despines, A. A., Toledo, F. G. S., et al. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00257.2014 · Cited by 83 · see citing works
The saturated fatty acid, palmitic acid, induces anxiety-like behavior in mice
Moon, M. L., Joesting, J. J., Lawson, M. A., Chiu, G. S., Blevins, N. A., Kwakwa, K. A., & Freund, G. G. (2014) · Metabolism · doi:10.1016/j.metabol.2014.06.002 · Cited by 82 · see citing works
Salvadego, D., Domenis, R., Lazzer, S., Porcelli, S., Rittweger, J., Rizzo, G., Mavelli, I., Šimunič, B., Pišot, R., & Grassi, B. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00883.2012 · Cited by 68 · see citing works
Crescenti, A., Bas-Prior, J. M. D., Arola‐Arnal, A., Oms‐Oliu, G., Arola, L., & Caimari, A. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2015.03.003 · Cited by 53 · see citing works
Omega-3 long-chain fatty acids strongly induce angiopoietin-like 4 in humans
Brands, M., Sauerwein, H. P., Ackermans, M. T., Kersten, S., & Serlie, M. J. M. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m030049 · Cited by 29 · see citing works
Self-citationTam, E., Bruseghini, P., Calabria, E., Sacco, L. D., Doria, C., Grassi, B., Pietrangelo, T., Pogliaghi, S., Reggiani, C., Salvadego, D., et al. (2015) · European Journal of Applied Physiology · doi:10.1007/s00421-015-3256-z · Cited by 23 · see citing works
Mathers, K. E., & Staples, J. F. (2015) · Biology Open · doi:10.1242/bio.011544 · Cited by 16 · see citing works
Role of Mitochondrial Function in Insulin Resistance
Brands, M., Verhoeven, A. J., & Serlie, M. J. M. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-94-007-2869-1_9 · Cited by 9 · see citing works
Self-citationBrands, M., van Raalte, D. H., Ferraz, M. J., Sauerwein, H. P., Verhoeven, A. J., Aerts, J. M. F. G., Diamant, M., & Serlie, M. J. M. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3266 · Cited by 8 · see citing works
Self-citationDoerrier, C., Gama-Pérez, P., Pesta, D. H., Distéfano, G., Soendergaard, S. D., Chrøis, K. M., González-Franquesa, A., Goodpaster, B. H., Prats, C., Sales‐Pardo, M., et al. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.07.039 · Cited by 7 · see citing works
Wang, X., Wu, L. J., Luo, H., Zhong, W., Zheng, X., & Xu, R. (2024) · Journal of obstetrics and gynaecology research · doi:10.1111/jog.16109 · Cited by 6 · see citing works
Nokoff, N., Nemkov, T. G., Bothwell, S., Cree‐Green, M., Fuller, K. N. Z., Keller, A. C., Kelsey, M. M., Nadeau, K. J., & Moreau, K. L. (2024) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00629.2024 · Cited by 4 · see citing works
Role of insulin receptor substrate 1 in energy homeostasis in vivo
Stöhr, O. (2012) · Kölner Universitäts PublikationsServer (Universität zu Köln)
- Authors
- Brands, M., Hoeks, J., Sauerwein, H. P., Ackermans, M. T., Ouwens, M., Lammers, N. M., van der Plas, M. N., Schrauwen, P., Groen, A. K., & Serlie, M. J.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Maastricht University Medical Centre (NL)
- Corresponding author
- Brands, Myrte
- Venue
- Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 60
- Issue
- 10
- Pages
- 1398-1405
- ISSN
- 0026-0495 (ISSN-L)
- OpenAlex
- W2162493960
- Cited by
- 19
- References
- 49
- Citations by year
- 2024: 3 · 2018: 1 · 2016: 1 · 2015: 4 · 2014: 2 · 2013: 4 · 2012: 1
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- 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
- plasma free fatty acids, insulin resistance, mitochondrial respiratory capacity, skeletal muscle, hyperinsulinemic-euglycemic clamp, Intralipid, lipid emulsions, glucose uptake, mitochondrial biogenesis, uncoupled respiration, ATP production
- MeSH terms
- Adult, Biopsy, Blood Glucose, Fatty Acids, Nonesterified, Health, Humans, Insulin, Insulin Resistance, Male, Mitochondria, Muscle, Oxidation-Reduction, Time Factors, Glucose Clamp Technique, Muscle, Skeletal, Cell Respiration, Young Adult
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