Increased Efficiency of Fatty Acid Uptake Contributes to Lipid Accumulation in Skeletal Muscle of High Fat-Fed Insulin-Resistant Rats
Open accessAbstract
In humans and animal models, increased lipid content of skeletal muscle is strongly associated with insulin resistance. However, it is unclear whether this accumulation is due to increased uptake or reduced utilization of fatty acids (FAs). We used 3H-R-bromopalmitate tracer to assess the contribution of tissue-specific changes in FA uptake to the lipid accumulation observed in tissues of insulin-resistant, high fat-fed rats (HFF) compared with control rats (CON) fed a standard diet. To study FA metabolism under different metabolic states, tracer was infused under basal conditions, during hyperinsulinemic-euglycemic clamp (low FA availability) or during the infusion of intralipid and heparin (high FA availability). FA clearance was significantly increased in the red gastrocnemius muscle of HFF under conditions of low (HFF = 10.4 ± 1.1; CON = 7.4 ± 0.5 ml · min−1 · 100 g−1; P < 0.05), basal (HFF = 8.3 ± 1.4; CON = 4.5 ± 0.7 ml · min−1 · 100 g−1; P < 0.01), and high (HFF = 7.0 ± 0.8; CON = 4.3 ± 0.5 ml · min−1 · 100 g−1; P < 0.05) FA levels. This indicates an adaptation by muscle for more efficient uptake of lipid. Associated with the enhanced efficiency of FA uptake, we observed increases in CD36/FA translocase mRNA expression (P < 0.01) and acyl-CoA synthetase activity (P < 0.02) in the same muscle. FA clearance into white adipose tissue was also increased in HFF when circulating FA were elevated, but there was little effect of the high-fat diet on hepatic FA uptake. In conclusion, insulin resistance induced by feeding rats a high-fat diet is associated with tissue-specific adaptations that enhance utilization of increased dietary lipid but could also contribute to the accumulation of intramuscular lipid with a detrimental effect on insulin action.
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?
Increased fatty acid uptake contributes to increased lipid accumulation in skeletal muscle, leading to lipotoxicity, which impairs muscle insulin sensitivity.
“Increased fatty acid (FA) uptake contributes to increased lipid accumulation in skeletal muscle, leading to lipotoxicity, which is known to impair muscle insulin sensitivity (2, 20).”
From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [20]
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
Randle, P. J., Garland, P. B., Hales, C. N., & Newsholme, E. A. (1963) · The Lancet · doi:10.1016/s0140-6736(63)91500-9 · Cited by 5,093 · see citing works
The Triumvirate: β-Cell, Muscle, Liver: A Collusion Responsible for NIDDM
DeFronzo, R. A. (1988) · Diabetes · doi:10.2337/diab.37.6.667 · Cited by 2,456 · see citing works
Griffin, M. E., Marcucci, M. J., Cline, G. W., Bell, K., Barucci, N., Lee, D., Goodyear, L. J., Kraegen, E. W., White, M. F., & Shulman, G. I. (1999) · Diabetes · doi:10.2337/diabetes.48.6.1270 · Cited by 1,267 · see citing works
Self-citationSkeletal Muscle Triglyceride Levels Are Inversely Related to Insulin Action
Pan, D. A., Lillioja, S., Kriketos, A. D., Milner, M. R., Baur, L. A., Bogardus, C., Jenkins, A. B., & Storlien, L. H. (1997) · Diabetes · doi:10.2337/diab.46.6.983 · Cited by 1,179 · see citing works
Skeletal muscle triglyceride levels are inversely related to insulin action
Pan, D. A., Lillioja, S., Kriketos, A. D., Milner, M. R., Baur, L. A., Bogardus, C., Jenkins, A. B., & Storlien, L. H. (1997) · Diabetes · doi:10.2337/diabetes.46.6.983 · Cited by 1,179 · see citing works
Kelley, D. E., Goodpaster, B., Wing, R. R., & Simoneau, J.-A. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.6.e1130 · Cited by 1,096 · see citing works
Storlien, L. H., Jenkins, A. B., Chisholm, D. J., Pascoe, W. S., Khouri, S., & Kraegen, E. W. (1991) · Diabetes · doi:10.2337/diab.40.2.280 · Cited by 967 · see citing works
Self-citationPerseghin, G., Scifo, P., De Cobelli, F., Pagliato, E., Battezzati, A., Arcelloni, C., Vanzulli, A., Testolin, G., Pozza, G., Del Maschio, A., et al. (1999) · Diabetes · doi:10.2337/diabetes.48.8.1600 · Cited by 877 · see citing works
Goodpaster, B. H., Thaete, F. L., & Kelley, D. E. (2000) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/71.4.885 · Cited by 707 · see citing works
What if Minkowski Had Been Ageusic? An Alternative Angle on Diabetes
McGarry, J. D. (1992) · Science · doi:10.1126/science.1439783 · Cited by 657 · see citing works
Direct antidiabetic effect of leptin through triglyceride depletion of tissues
Shimabukuro, M., Koyama, K., Chen, G., Wang, M.-Y., Trieu, F., Lee, Y., Newgard, C. B., & Unger, R. H. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.9.4637 · Cited by 646 · see citing works
Development of Muscle Insulin Resistance After Liver Insulin Resistance in High-Fat–Fed Rats
Kraegen, E. W., Clark, P. W., Jenkins, A. B., Daley, E. A., Chisholm, D. J., & Storlien, L. H. (1991) · Diabetes · doi:10.2337/diab.40.11.1397 · Cited by 601 · see citing works
Self-citationThe Sevenfold Way of PKC Regulation
Liu, W. S., & Heckman, C. A. (1998) · Cellular Signalling · doi:10.1016/s0898-6568(98)00012-6 · Cited by 487 · see citing works
Ryysy, L., Häkkinen, A. M., Goto, T., Vehkavaara, S., Westerbacka, J., Halavaara, J., & Yki-Järvinen, H. (2000) · Diabetes · doi:10.2337/diabetes.49.5.749 · Cited by 431 · see citing works
Mechanisms of Liver and Muscle Insulin Resistance Induced by Chronic High-Fat Feeding
Oakes, N. D., Cooney, G. J., Camilleri, S., Chisholm, D. J., & Kraegen, E. W. (1997) · Diabetes · doi:10.2337/diab.46.11.1768 · Cited by 414 · see citing works
Self-citationKelley, D. E., & Goodpaster, B. H. (2001) · Diabetes Care · doi:10.2337/diacare.24.5.933 · Cited by 406 · see citing works
Phillips, D. I. W., Caddy, S., Ilic, V., Fielding, B. A., Frayn, K. N., Borthwick, A. C., & Taylor, R. (1996) · Metabolism · doi:10.1016/s0026-0495(96)90260-7 · Cited by 390 · see citing works
Schmitz-Peiffer, C., Browne, C. L., Oakes, N. D., Watkinson, A., Chisholm, D. J., Kraegen, E. W., & Biden, T. J. (1997) · Diabetes · doi:10.2337/diab.46.2.169 · Cited by 314 · see citing works
Self-citationLewin, T. M., Kim, J.-H., Granger, D. A., Vance, J. E., & Coleman, R. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102036200 · Cited by 284 · see citing works
Abumrad, N. (1999) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(99)00137-7 · Cited by 277 · see citing works
Ellis, B. A., Poynten, A., Lowy, A. J., Furler, S. M., Chisholm, D. J., Kraegen, E. W., & Cooney, G. J. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.3.e554 · Cited by 273 · see citing works
Self-citationSignalling aspects of insulin resistance in skeletal muscle
Schmitz‐Peiffer, C. (2000) · Cellular Signalling · doi:10.1016/s0898-6568(00)00110-8 · Cited by 268 · see citing works
High-Fat Feeding Impairs Insulin-Stimulated GLUT4 Recruitment via an Early Insulin-Signaling Defect
Zierath, J. R., Houseknecht, K. L., Gnudi, L., & Kahn, B. B. (1997) · Diabetes · doi:10.2337/diab.46.2.215 · Cited by 238 · see citing works
Storlien, L. H., Jenkins, A. B., Chisholm, D. J., Pascoe, W. S., Khouri, S., & Kraegen, E. W. (1991) · Diabetes · doi:10.2337/diabetes.40.2.280 · Cited by 229 · see citing works
Self-citationHeart CD36 expression is increased in murine models of diabetes and in mice fed a high fat diet.
Greenwalt, D. E., Scheck, S., & Rhinehart-Jones, T. R. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118173 · Cited by 181 · see citing works
Oakes, N. D., Bell-Anderson, K. S., Furler, S. M., Camilleri, S., Saha, A. K., Ruderman, N. B., Chisholm, D. J., & Kraegen, E. W. (1997) · Diabetes · doi:10.2337/diab.46.12.2022 · Cited by 176 · see citing works
Self-citationOakes, N. D., Bell, K. S., Furler, S. M., Camilleri, S., Saha, A. K., Ruderman, N. B., Chisholm, D. J., & Kraegen, E. W. (1997) · Diabetes · doi:10.2337/diabetes.46.12.2022 · Cited by 176 · see citing works
Self-citationMajumdar, S., Rossi, M. W., Fujiki, T., Phillips, W. A., Disa, S., Queen, C. F., Johnston, R. B., Rosen, O. M., Corkey, B. E., & Korchak, H. M. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)31582-5 · Cited by 162 · see citing works
Decreased Susceptibility to Fatty Acid–Induced Peripheral Tissue Insulin Resistance in Women
Frias, J. P., Macaraeg, G. B., Ofrecio, J., Yu, J. G., Olefsky, J. M., & Kruszynska, Y. T. (2001) · Diabetes · doi:10.2337/diabetes.50.6.1344 · Cited by 162 · see citing works
Homan, R., & Anderson, M. K. (1998) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(97)00651-8 · Cited by 159 · see citing works
Alberti, K. G. M. M., & Krall, L. P. (1985) · Elsevier eBooks · Cited by 155 · see citing works
In vivo insulin sensitivity in the rat determined by euglycemic clamp
Kraegen, E. W., James, D. E., Bennett, S. P., & Chisholm, D. J. (1983) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1983.245.1.e1 · Cited by 153 · see citing works
Self-citationThompson, A. L., & Cooney, G. J. (2000) · Diabetes · doi:10.2337/diabetes.49.11.1761 · Cited by 132 · see citing works
Self-citationQu, X.-Q., Seale, J., & Donnelly, R. (1999) · Journal of Endocrinology · doi:10.1677/joe.0.1620207 · Cited by 123 · see citing works
Oakes, N. D., Camilleri, S., Furler, S. M., Chisholm, D. J., & Kraegen, E. W. (1997) · Metabolism · doi:10.1016/s0026-0495(97)90083-4 · Cited by 121 · see citing works
Self-citationIntravenous lipid emulsions: removal mechanisms as compared to chylomicrons.
Hultin, M., Carneheim, C., Rosenqvist, K., & Olivecrona, T. (1996) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39201-4 · Cited by 118 · see citing works
Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding
Oakes, N. D., Cooney, G. J., Camilleri, S., et al. (1997) · Diabetes · doi:10.2337/diabetes.46.11.1768 · Cited by 118 · see citing works
Self-citationLaybutt, D. R., Schmitz‐Peiffer, C., Saha, A. K., Ruderman, N. B., Biden, T. J., & Kraegen, E. W. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.6.e1070 · Cited by 114 · see citing works
Self-citationPerseghin, G., Scifo, P., Pagliato, E., Battezzati, A., Benedini, S., Soldini, L., Testolin, G., Maschio, A. D., & Luzi, L. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.7.7666 · Cited by 110 · see citing works
Five-hour fatty acid elevation increases muscle lipids and impairs glycogen synthesis in the rat
Chalkley, S. M., Hettiarachchi, M., Chisholm, D. J., & Kraegen, E. W. (1998) · Metabolism · doi:10.1016/s0026-0495(98)90287-6 · Cited by 109 · see citing works
Self-citationEffects of individual fatty acids on glucose uptake and glycogen synthesis in soleus muscle in vitro
Thompson, A. L., Lim-Fraser, M. Y.-C., Kraegen, E. W., & Cooney, G. J. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.3.e577 · Cited by 107 · see citing works
Self-citationTurcotte, L. P., Swenberger, J. R., Zavitz Tucker, M., & Yee, A. J. (2001) · Diabetes · doi:10.2337/diabetes.50.6.1389 · Cited by 100 · see citing works
Schmitz‐Peiffer, C., Browne, C. L., Oakes, N. D., Watkinson, A., Chisholm, D. J., Kraegen, E. W., & Biden, T. J. (1997) · Diabetes · doi:10.2337/diabetes.46.2.169 · Cited by 89 · see citing works
Self-citationChen, M.-T., Kaufman, L. N., Spennetta, T., & Shrago, E. (1992) · Metabolism · doi:10.1016/0026-0495(92)90221-u · Cited by 83 · see citing works
Fabris, R., Nisoli, E., Lombardi, A. M., Tonello, C., Serra, R., Granzotto, M., Cusin, I., Rohner‐Jeanrenaud, F., Federspil, G., Carruba, M. O., et al. (2001) · Diabetes · doi:10.2337/diabetes.50.3.601 · Cited by 79 · see citing works
Regulation of fatty acid transporters in mammalian cells
Frohnert, B. I., & Bernlohr, D. (2000) · Progress in Lipid Research · doi:10.1016/s0163-7827(99)00018-1 · Cited by 76 · see citing works
Pentobarbital reduces basal liver glucose output and its insulin suppression in rats
Clark, P. W., Jenkins, A. B., & Kraegen, E. W. (1990) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1990.258.4.e701 · Cited by 62 · see citing works
Self-citationShafrir, E., & Ziv, E. (1998) · Journal of Basic and Clinical Physiology and Pharmacology · doi:10.1515/jbcpp.1998.9.2-4.347 · Cited by 57 · see citing works
Oakes, N. D., Kjellstedt, A., Forsberg, G., Clementz, T., Camejo, G., Furler, S. M., Kraegen, E. W., Ölwegård-Halvarsson, M., Jenkins, A. B., & Ljung, B. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33520-3 · Cited by 54 · see citing works
Self-citationOrellana, A., HIDALGO, P. C., Morales, M. N., Mezzano, D., & Bronfman, M. (1990) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1990.tb15545.x · Cited by 52 · see citing works
Furler, S. M., Cooney, G. J., Hegarty, B. D., Lim-Fraser, M., Kraegen, E. W., & Oakes, N. D. (2000) · Diabetes · doi:10.2337/diabetes.49.9.1427 · Cited by 50 · see citing works
Self-citationLaybutt, D. R., Chisholm, D. J., & Kraegen, E. W. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.273.1.e1 · Cited by 47 · see citing works
Self-citationNesher, M., & Boneh, A. (1994) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/0167-4889(94)90217-8 · Cited by 32 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
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
Excess Lipid Availability Increases Mitochondrial Fatty Acid Oxidative Capacity in Muscle
Turner, N., Bruce, C. R., Beale, S. M., Hoehn, K. L., So, T., Rolph, M. S., & Cooney, G. J. (2007) · Diabetes · doi:10.2337/db07-0093 · Cited by 520 · see citing works
Self-citationBruce, C. R., Hoy, A. J., Turner, N., Watt, M. J., Allen, T. L., Carpenter, K., Cooney, G. J., Febbraio, M. A., & Kraegen, E. W. (2009) · Diabetes · doi:10.2337/db08-1078 · Cited by 363 · see citing works
Self-citationAMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity.
O’Neill, H. M., Holloway, G. P., & Steinberg, G. R. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.019 · Cited by 364 · see citing works
Link between obesity and type 2 diabetes
Golay, A., & Ybarra, J. (2005) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2005.07.010 · Cited by 301 · see citing works
Targeting fatty acid metabolism to improve glucose metabolism
Stinkens, R., Goossens, G. H., Jocken, J. W. E., & Blaak, E. E. (2015) · Obesity Reviews · doi:10.1111/obr.12298 · Cited by 183 · 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
Miljkovic, I., Kuipers, A. L., Cauley, J. A., Prasad, T., Lee, C. G., Ensrud, K. E., Cawthon, P. M., Hoffman, A. R., Dam, T.-T., Gordon, C. L., et al. (2015) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glv027 · Cited by 144 · see citing works
Myosteatosis increases with aging and is associated with incident diabetes in African ancestry men
Miljkovic, I., Kuipers, A. L., Cvejkus, R., Bunker, C. H., Patrick, A. L., Gordon, C. L., & Zmuda, J. M. (2016) · Obesity · doi:10.1002/oby.21328 · Cited by 89 · see citing works
DiMenna, F. J., & Arad, A. D. (2018) · BMC Sports Science, Medicine and Rehabilitation · doi:10.1186/s13102-018-0110-8 · Cited by 68 · see citing works
PPARs and the orchestration of metabolic fuel selection
Sugden, M. C., Zariwala, M. G., & Holness, M. J. (2009) · Pharmacological Research · doi:10.1016/j.phrs.2009.03.014 · Cited by 64 · see citing works
The impact of a high-fat diet in mice is dependent on duration and age, and differs between muscles
Messa, G. A. M., Piasecki, M., Hurst, J., Hill, C., Tallis, J., & Degens, H. (2020) · Journal of Experimental Biology · doi:10.1242/jeb.217117 · Cited by 63 · see citing works
Muscle insulin resistance: a case of fat overconsumption, not mitochondrial dysfunction
Kraegen, E. W., Cooney, G. J., & Turner, N. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803901105 · Cited by 62 · see citing works
Self-citationBeck Jørgensen, S., O’Neill, H. M., Hewitt, K., Kemp, B. E., & Steinberg, G. R. (2009) · Diabetologia · doi:10.1007/s00125-009-1483-8 · Cited by 42 · see citing works
Role of lipid-derived mediators in skeletal muscle insulin resistance
Taube, A., Eckardt, K., & Eckel, J. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00241.2009 · Cited by 40 · see citing works
- Authors
- Hegarty, B. D., Cooney, G. J., Kraegen, E. W., & Furler, S. M.
- Affiliations
- Garvan Institute of Medical Research (AU)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2002-05-01
- Volume
- 51
- Issue
- 5
- Pages
- 1477-1484
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2111575442
- Cited by
- 166
- References
- 53
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 7 · 2021: 3 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 6 · 2016: 8 · 2015: 9 · 2014: 7 · 2013: 9 · 2012: 13
- FWCI
- 4.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- insulin resistance, high-fat diet, fatty acid uptake, skeletal muscle lipid accumulation, intramuscular fat, CD36, fatty acid translocase, acyl-CoA synthetase, white adipose tissue, hepatic fatty acid uptake, hyperinsulinemic-euglycemic clamp, gastrocnemius
- MeSH terms
- Adipose Tissue, Animals, Body Weight, Dietary Fats, Eating, Fatty Acids, Insulin, Insulin Resistance, Male, RNA, Messenger, Gene Expression, Rats, Wistar, Muscle, Skeletal, Muscle Fibers, Fast-Twitch, CD36 Antigens, Rats
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
