Role of intramyocelluar lipids in human health
Open accessAbstract
Intramyocellular lipid (IMCL) is predominantly stored as intramuscular triglyceride (IMTG) in lipid droplets and is utilized as metabolic fuel during physical exercise. IMTG is also implicated in muscle insulin resistance (IR) in type 2 diabetes. However, it has become apparent that lipid moieties such as ceramide and diacylglycerol are the likely culprits of IR. This article reviews current knowledge of IMCL-mediated IR and important areas of investigation, including myocellular lipid transport and lipid droplet proteins. Several crucial questions remain unanswered, such as the identity of specific ceramide and diacylglycerol species that mediate IR in human muscle and their subcellular location. Quantitative lipidomics and proteomics of targeted subcellular organelles will help to better define the mechanisms underlying pathological IMCL accumulation and IR.
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Exercise-induced improvements in insulin sensitivity arise from many different alterations.
“Improvements in insulin sensitivity with exercise are induced by a myriad of alterations (34–37), while our data suggest that improvements in cellular redox status play a prominent role.”
From Defects in mitochondrial efficiency and H2O2 emissions in obese women are restored to a lean phenotype with aerobic exercise training (2015) · cites this paper as [36]
Enhanced mitochondrial content and function can sustain greater energetic flux and oxidation of substrates, decreasing the accumulation of lipotoxic intermediates that promote inflammation and oxidative stress.
“Enhanced mitochondrial content and function can sustain greater energetic flux and oxidation of substrates, decreasing the accumulation of lipotoxic intermediates that promote inflammation and oxidative stress [382].”
From Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR) (2025) · cites this paper as [382]
The link between intramyocellular lipid and insulin resistance was confirmed in biopsies from individuals with obesity and type 2 diabetes mellitus.
“The link between IMCL and insulin resistance was confirmed in biopsies from individuals with obesity and T2DM (Goodpaster et al, 2000; Coen & Goodpaster, 2012).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Coen & Goodpaster, 2012
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Shaw, C. S., Sherlock, M., Stewart, P. M., & Wagenmakers, A. J. M. (2009) · Histochemistry and Cell Biology · doi:10.1007/s00418-009-0558-4 · Cited by 59 · see citing works
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High triacylglycerol turnover rate in human skeletal muscle
Sacchetti, M., Saltin, B., Olsen, D. B., & van Hall, G. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2004.075135 · Cited by 50 · see citing works
The ceramide transporter and the Goodpasture antigen binding protein: one protein – one function?
Mencarelli, C., Losen, M., Hammels, C., et al. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06673.x · Cited by 40 · see citing works
Impaired ?-adrenergically mediated lipolysis in skeletal muscle of obese subjects
Blaak, E. E., Schiffelers, S. L. H., Saris, W. H. M., Mensink, M., & Kooi, M. E. (2004) · Diabetologia · doi:10.1007/s00125-004-1471-y · Cited by 38 · see citing works
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Assessment of intramuscular triglycerides: contribution to metabolic abnormalities
Dubé, J., & Goodpaster, B. H. (2006) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/01.mco.0000241664.38385.12 · Cited by 31 · see citing works
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The twists and turns of sphingolipid pathway in glucose regulation
Deevska, G. M., & Nikolova‐Karakashian, M. (2010) · Biochimie · doi:10.1016/j.biochi.2010.05.016 · Cited by 29 · see citing works
Thrush, A. B., Harasim‐Symbor, E., Chabowski, A., Gulli, R. A., Stefanyk, L. E., & Dyck, D. J. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00091.2010 · Cited by 24 · see citing works
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Research works printed but not linked: 2
- [46]Stratford S Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J. Biol. Chem 2004 279 36608 36615 15220355
- [49]Novgorodov SA Novel pathway of ceramide production in mitochondria: thioesterase and neutral ceramidase produce ceramide from sphingosine and acyl-CoA. J. Biol. Chem 2011 286 25352 25362 21613224 PMC3137106
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Sorted by citations
Kalinkovich, A., & Livshits, G. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.09.008 · Cited by 882 · see citing works
Sugar consumption, metabolic disease and obesity: The state of the controversy
Stanhope, K. L. (2016) · Critical Reviews in Clinical Laboratory Sciences · doi:10.3109/10408363.2015.1084990 · Cited by 739 · see citing works
“It is also possible that other factors such as inflammation and oxidative stress (51), are contributors to, or possibly mediators of, muscle insulin resistance (52).”
Intermuscular fat: a review of the consequences and causes
Addison, O., Marcus, R. L., LaStayo, P. C., & Ryan, A. S. (2014) · International Journal of Endocrinology · doi:10.1155/2014/309570 · Cited by 656 · see citing works
“While not frequently isolated as a separate fat depot by itself, there also exists a smaller group of lipids stored within the muscle cells themselves known as intramyocellular lipids or IMCL; IMCL has been reviewed extensively elsewhere [47].”
BackgroundObesity-Associated Oxidative Stress: Strategies Finalized to Improve Redox State
Savini, I., Catani, M. V., Evangelista, D., Gasperi, V., & Avigliano, L. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140510497 · Cited by 514 · see citing works
“Ectopic-fat deposition blocks glucose transport and insulin signaling: lipid accumulation in skeletal muscle has been associated with altered insulin sensitivity [87] and tissues from obese patients are resistant to the action of insulin [71].”
BackgroundResveratrol and diabetes: from animal to human studies.
Szkudelski, T., & Szkudelska, K. (2015) · Biochimica et Biophysica Acta · doi:10.1016/j.bbadis.2014.10.013 · Cited by 322 · see citing works
Ceramides in Metabolism: Key Lipotoxic Players
Chaurasia, B., & Summers, S. A. (2020) · Annual Review of Physiology · doi:10.1146/annurev-physiol-031620-093815 · Cited by 357 · see citing works
“In skeletal muscle, Goodpaster and colleagues (71-74) identified positive correlations between muscle ceramides and insulin resistance in a large number of separate studies.”
BackgroundSkeletal muscle insulin resistance: role of mitochondria and other ROS sources
Di Meo, S., Iossa, S., & Venditti, P. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0598 · Cited by 282 · see citing works
“Accordingly, the amount of skeletal muscle ceramides, which are responsible for the impairment of insulin signaling (Coen & Goodpaster 2012), is increased with lipid-rich diet and is even higher with lipid-rich, fructose-rich diet (Crescenzo et al .”
BackgroundIzquierdo, M., de Souto Barreto, P., Arai, H., Bischoff-Ferrari, H. A., Cadore, E. L., Cesari, M., Chen, L.-K., Coen, P. M., Courneya, K. S., Duque, G., et al. (2025) · The Journal of nutrition, health and aging · doi:10.1016/j.jnha.2024.100401 · Cited by 273 · see citing works
Self-citationKimmel, A. R., & Sztalryd, C. (2016) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071813-105410 · Cited by 285 · see citing works
Metabolic Messengers: ceramides
Summers, S. A., Chaurasia, B., & Holland, W. L. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0134-8 · Cited by 304 · see citing works
HOCKING, S. L., Samocha‐Bonet, D., Milner, K., Greenfield, J. R., & Chisholm, D. J. (2013) · Endocrine Reviews · doi:10.1210/er.2012-1041 · Cited by 281 · see citing works
Mitochondrial and cellular mechanisms for managing lipid excess
Aon, M. A., Bhatt, N., & Cortassa, S. C. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00282 · Cited by 253 · see citing works
“Previous reports have linked ROS-mediated mitochondrial dysfunction to DAG and ceramide, two main products of lipid degradation (Coen and Goodpaster, 2012).”
BackgroundWhite, P., Lapworth, A., An, J., Wang, L.-P., McGarrah, R., Stevens, R., Ilkayeva, O., George, T., Muehlbauer, M., Bain, J. R., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.04.006 · Cited by 253 · see citing works
“Furthermore, changes in protein acylation states secondary to changes in the acyl CoA pool and/ or reduced formation of lipid derivatives such as diacylglycerol and ceramide could also have contributed to improved insulin sensitivity in BCAA-restricted ZFR [36,37].”
BackgroundThe effects of obesity on skeletal muscle regeneration
Akhmedov, D., & Berdeaux, R. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00371 · Cited by 241 · see citing works
“In skeletal muscle, lipotoxic species interfere with insulin signaling and are thought to be partly responsible for insulin resistance in obesity (reviewed in Timmers et al., 2008; Bosma et al., 2012; Coen and Goodpaster, 2012).”
BackgroundLooijaard, W. G. P. M., Dekker, I. M., Stapel, S. N., Girbes, A. R. J., Twisk, J. W. R., Oudemans-van Straaten, H. M., & Weijs, P. J. M. (2016) · Critical Care · doi:10.1186/s13054-016-1563-3 · Cited by 218 · see citing works
“These inflammatory cells produce proinflammatory cytokines such as tumour necrosis factoralpha (TNFα) and interleukin-6 (IL-6) [35] which mediate contractile dysfunction [36, 37] and create a low-grade inflammatory environment in which the metabolic syndrome, cardiovascular disease, and insulin resistance are prone to…”
BackgroundDecoding Insulin Resistance and Metabolic Syndrome for Promising Therapeutic Intervention
Guo, S. (2014) · Journal of Endocrinology · doi:10.1530/joe-13-0584 · Cited by 215 · see citing works
Fatty acid metabolism, energy expenditure and insulin resistance in muscle
Turner, N. A., Cooney, G. J., Kraegen, E. W., & Bruce, C. R. (2013) · Journal of Endocrinology · doi:10.1530/joe-13-0397 · Cited by 198 · see citing works
Impact of different ectopic fat depots on cardiovascular and metabolic diseases
Ferrara, D., Montecucco, F., Dallegri, F., & Carbone, F. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28821 · Cited by 195 · see citing works
“…IRS‐1 and PI3K, ultimately downregulating GLUT4 translocation; the same effect is thought to be triggered by ceramides via inhibition of Akt/PKB, involving protein phosphatase 2A (PP2A) and PKC‐ζ as intermediate effectors (Coen & Goodpaster, 2012; Gemmink et al., 2017; Kitessa & Abeywardena, 2016).”
BackgroundResultInfluentialIntermuscular and intramuscular adipose tissues: Bad vs. good adipose tissues
Hausman, G., Basu, U., Du, M., Fernyhough-culver, M., & Dodson, M. (2014) · Adipocyte · doi:10.4161/adip.28546 · Cited by 189 · see citing works
“Additionally, IMCL can be quantified with lipid histochemistry of muscle biopsies with or without 1HMRS.(78) The influence of race, aging, physical activity and obesity on INTMF and muscle changes are summarized in Table 1.”
BackgroundInfluentialEffects of growth hormone on glucose metabolism and insulin resistance in human
Kim, S.-H., & Park, M.-J. (2017) · Annals of Pediatric Endocrinology & Metabolism · doi:10.6065/apem.2017.22.3.145 · Cited by 181 · see citing works
Tonks, K., Coster, A., Christopher, M., Chaudhuri, R., Xu, A., Gagnon-Bartsch, J., Chisholm, D., James, D. E., Meikle, P., Greenfield, J., et al. (2016) · Obesity · doi:10.1002/oby.21448 · Cited by 162 · see citing works
“Cer is the “hub” lipid in sphingolipid metabolism, serving as a precursor for sphingomyelin (SM) and the higher order sphingolipids monohexosylceramide (MHC/ HexCer), dihexosylceramide (DHC/Hex2Cer), trihexosylcermide (THC/Hex3Cer), and GM3 ganglioside (GM3) and generated de novo from dihydroceramide (dhCer) or breakd…”
BackgroundWhole body fat: Content and distribution
Thomas, E. L., Fitzpatrick, J. A., Malik, S., Taylor-Robinson, S. D., & Bell, J. D. (2013) · Progress in Nuclear Magnetic Resonance Spectroscopy · doi:10.1016/j.pnmrs.2013.04.001 · Cited by 170 · see citing works
“This apparent contradiction has necessitated a rethink regarding whether elevated IMCL actually causes insulin resistance, or is a secondary effect [182].”
BackgroundSztalryd, C., & Kimmel, A. (2013) · Biochimie · doi:10.1016/j.biochi.2013.08.026 · Cited by 158 · see citing works
“Skeletal muscle from exercised-trained subjects can display high insulin sensitivity, despite intramuscular TAG levels that exceed those of obese and diabetic individuals, a phenomenon described as the “athlete paradox” [4,5].”
BackgroundBouret, S., Levin, B. E., & Ozanne, S. E. (2015) · Physiological Reviews · doi:10.1152/physrev.00007.2014 · Cited by 157 · see citing works
The Limits of Exercise Physiology: From Performance to Health
Gabriel, B. M., & Zierath, J. R. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.018 · Cited by 188 · see citing works
“Conversely, trained endurance athletes have high intra-muscular lipid content, but excellent insulin sensitivity, which may be partly explained by increased turnover of intra-muscular lipid pools and protection against reactive oxygen species (Coen and Goodpaster, 2012).”
BackgroundCoen, P. M., Menshikova, E. V., Distéfano, G., Zheng, D., Tanner, C., Standley, R., Helbling, N., Dubis, G. S., Ritov, V., Xie, H., et al. (2015) · Diabetes · doi:10.2337/db15-0809 · Cited by 155 · see citing works
Self-citationChakrabarti, P., Kim, J. Y., Singh, M., Shin, Y., Kim, J., Kumbrink, J., Wu, Y., Lee, M., Kirsch, K. H., Fried, S. K., et al. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01584-12 · Cited by 176 · see citing works
Cabodevilla, A. G., Sánchez-Caballero, L., Nintou, E., Boiadjieva, V. G., Picatoste, F., Gubern, A., & Claro, E. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.466656 · Cited by 154 · see citing works
Kemp, G. J., Ahmad, R., Nicolay, K., & Prompers, J. J. (2014) · Acta Physiologica · doi:10.1111/apha.12307 · Cited by 158 · see citing works
“…of muscle mitochondrial function and lipid metabolism in the pathophysiology of insulin resistance in general, and Type 2 diabetes specifically, is muchdebated: two recent reviews examine the possible mechanisms in detail (Coen & Goodpaster 2012, © 2014 Scandinavian Physiological Society.”
BackgroundMuscle sphingolipids during rest and exercise: a C18:0 signature for insulin resistance in humans
Bergman, B. C., Brozinick, J. T., Strauss, A., Bacon, S., Kerege, A., Bui, H. H., Sanders, P., Siddall, P., Wei, T., Thomas, M. K., et al. (2016) · Diabetologia · doi:10.1007/s00125-015-3850-y · Cited by 148 · see citing works
Mitochondrial response to nutrient availability and its role in metabolic disease
Gao, A. W., Cantó, C., & Houtkooper, R. H. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201303782 · Cited by 148 · see citing works
“The link between IMCL and insulin resistance was confirmed in biopsies from individuals with obesity and T2DM (Goodpaster et al , 2000; Coen & Goodpaster, 2012).”
Food Polyphenols and Type II Diabetes Mellitus: Pharmacology and Mechanisms
Naz, R., Saqib, F., Awadallah, S. M., Wahid, M., Latif, M. F., Iqbal, I., & Mubarak, M. S. (2023) · Molecules · doi:10.3390/molecules28103996 · Cited by 175 · see citing works
Mitochondria as a Target for Mitigating Sarcopenia
Coen, P. M., Musci, R., Hinkley, J., & Miller, B. F. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2018.01883 · Cited by 140 · see citing works
“Increased energetic flux can decrease the accumulation of lipotoxic intermediates that promote inflammation and oxidative stress (Goodpaster et al., 2001b; Coen and Goodpaster, 2012).”
BackgroundSelf-citationPerilipin 5, a Lipid Droplet Protein Adapted to Mitochondrial Energy Utilization
Kimmel, A., & Sztalryd, C. (2014) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000057 · Cited by 127 · see citing works
Mitochondrial Deficiency Is Associated With Insulin Resistance
Goodpaster, B. (2013) · Diabetes · doi:10.2337/db12-1612 · Cited by 123 · see citing works
“More recently, a prevalent hypothesis has been put forth to link mitochondria with IR, whereby lower mitochondrial content or impairments in mitochondrial fatty acid oxidation lead to excess accumulation of intramyocellular lipids, most notably diacylglycerol and ceramides (15).”
BackgroundSelf-citationGlucocorticoid-Induced Fatty Liver Disease
Rahimi, L., Rajpal, A., & Ismail‐Beigi, F. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s247379 · Cited by 148 · see citing works
Konopka, A. R., Asante, A., Lanza, I. R., Robinson, M. M., Johnson, M. L., Dalla Man, C., Cobelli, C., Amols, M. H., Irving, B. A., & Nair, K. S. (2015) · Diabetes · doi:10.2337/db14-1701 · Cited by 112 · see citing works
Interplay of skeletal muscle and adipose tissue: sarcopenic obesity.
Park, M., & Choi, K. M. (2023) · Metabolism: Clinical and Experimental · doi:10.1016/j.metabol.2023.155577 · Cited by 106 · see citing works
Omics and Exercise: Global Approaches for Mapping Exercise Biological Networks.Preprint
Hoffman, N. J. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a029884 · Cited by 106 · see citing works
Gustafson, B., & Smith, U. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.04.812 · Cited by 112 · see citing works
Short‐term disuse promotes fatty acid infiltration into skeletal muscle
Pagano, A. F., Brioche, T., Arc-Chagnaud, C., Demangel, R., Chopard, A., & Py, G. (2017) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12259 · Cited by 99 · see citing works
Targeting ceramide metabolism in obesity.
Aburasayn, H., Batran, R. A., & Ussher, J. (2016) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00133.2016 · Cited by 94 · see citing works
“Furthermore, these observations in animals appear to be translationally relevant to humans, as skeletal muscle biopsies from obese insulin-resistant humans and/or patients with T2D also demonstrate an elevation in ceramide content that inversely correlates with their overall insulin sensitivity (23).”
BackgroundLipid droplet dynamics in skeletal muscle
Bosma, M. (2016) · Experimental Cell Research · doi:10.1016/j.yexcr.2015.10.023 · Cited by 91 · see citing works
Role of Thigh Muscle Changes in Knee Osteoarthritis Outcomes: Osteoarthritis Initiative Data.
Mohajer, B., Dolatshahi, M., Moradi, K., Najafzadeh, N., Eng, J., Zikria, B., Wan, M., Cao, X., Roemer, F., Guermazi, A., et al. (2022) · Radiology · doi:10.1148/radiol.212771 · Cited by 91 · see citing works
Exploring the Impact of Obesity on Skeletal Muscle Function in Older Age
Morgan, P., Smeuninx, B., & Breen, L. (2020) · Frontiers in Nutrition · doi:10.3389/fnut.2020.569904 · Cited by 90 · see citing works
“) may associate more closely with age-related muscle anabolic resistance (217).”
BackgroundImaging methods for analyzing body composition in human obesity and cardiometabolic disease
Seabolt, L., Welch, E., & Silver, H. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12842 · Cited by 87 · see citing works
Jocken, J. W. E., Goossens, G. H., Boon, H., Mason, R. R., Essers, Y. P. G., Havekes, B., Watt, M. J., van Loon, L. J. C., & Blaak, E. E. (2013) · Diabetologia · doi:10.1007/s00125-013-2995-9 · Cited by 89 · see citing works
“Skeletal muscle (SM) lipid accumulation, and more specifically the accumulation of lipid metabolites, is strongly associated with the development of insulin resistance in the obese or obese type 2 diabetic state [1].”
BackgroundLehti, M., Donelan, E. M., Abplanalp, W., Al-Massadi, O., Habegger, K., Weber, J., Ress, C., Mansfeld, J., Somvanshi, S., Trivedi, C. J., et al. (2013) · Circulation · doi:10.1161/circulationaha.113.001551 · Cited by 84 · see citing works
“Finally, an excessive conversion of glucose into lipid resulting from defects in mitochondrial function leads to accumulation of intramyocellular triglycerides, which also has been implicated in insulin resistance in several population studies.(21) Although it has been shown that HDL and apoA-I do increase glucose upt…”
BackgroundSkeletal Muscle Triacylglycerol Hydrolysis Does Not Influence Metabolic Complications of Obesity
Sitnick, M., Basantani, M., Cai, L., Schoiswohl, G., Yazbeck, C. F., Distéfano, G., Ritov, V., DeLany, J., Schreiber, R., Stolz, D., et al. (2013) · Diabetes · doi:10.2337/db13-0500 · Cited by 80 · see citing works
“Since skeletal muscle is the major contributor to insulinmediated glucose disposal, lipid excess in this tissue could have serious implications for systemic glucose homeostasis and insulin responsiveness (7).”
BackgroundSelf-citationSkeletal Muscle Dysfunction in the Development and Progression of Nonalcoholic Fatty Liver Disease
Altajar, S., & Baffy, G. (2020) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2020.00065 · Cited by 70 · see citing works
“Intramyocellular fat is not necessarily abnormal as it serves as an energy source to fuel muscle contraction.(8,20) The”
BackgroundHansen, S., Svendsen, P., Jeppesen, J., Høeg, L. D., Andersen, N. R., Kristensen, J. M., Nilas, L., Lundsgaard, A., Wojtaszewski, J., Madsbad, S., et al. (2018) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2018-01771 · Cited by 69 · see citing works
MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling.
Ahn, B., Soundarapandian, M. M., Sessions, H., Peddibhotla, S., Roth, G., Li, J.-L., Sugarman, E., Koo, A., Malany, S., Wang, M., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci87382 · Cited by 63 · see citing works
Mitochondrial efficiency and insulin resistance
Crescenzo, R., Bianco, F., Mazzoli, A., Giacco, A., Liverini, G., & Iossa, S. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2014.00512 · Cited by 62 · see citing works
“In agreement with this suggestion, the content of skeletal muscle ceramides (known to be mediators of altered insulin signaling, Coen and Goodpaster, 2012) is higher in rats fed high-fat diet but even higher in rats fed high-fat-high fructose diet and therefore it is possible that in the latter…”
BackgroundPedroso, M., de Almeida, A. C., Aily, J., de Noronha, M. D., & Mattiello, S. (2019) · Rheumatology International · doi:10.1007/s00296-019-04271-2 · Cited by 61 · see citing works
Skeletal intramyocellular lipid metabolism and insulin resistance
Li, Y., Xu, S.-M., Zhang, X.-L., Yi, Z., & Cichello, S. (2015) · Biophysics Reports · doi:10.1007/s41048-015-0013-0 · Cited by 61 · see citing works
“Ceramide is also linked to mitochondrial dysfunction (Smith et al. 2013), which in turn is implicated in IMCL accumulation and IR (Coen and Goodpaster 2012).”
BackgroundTakeno, K., Tamura, Y., Kawaguchi, M., Kakehi, S., Watanabe, T., Funayama, T., Furukawa, Y., Kaga, H., Yamamoto, R., Kim, M., et al. (2016) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2016-1650 · Cited by 58 · see citing works
Skeletal Muscle and Bone – Emerging Targets of Fibroblast Growth Factor-21
Sun, H., Sherrier, M. C., & Li, H. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.625287 · Cited by 54 · see citing works
Waters, D. (2019) · Annals of Geriatric Medicine and Research · doi:10.4235/agmr.19.0001 · Cited by 56 · see citing works
Effect of exercise on myosteatosis in adults: a systematic review and meta-analysis.
Ramírez-Vélez, R., Ezzatvar, Y., Izquierdo, M., & García-Hermoso, A. (2020) · Journal of applied physiology · doi:10.1152/japplphysiol.00738.2020 · Cited by 54 · see citing works
“The inconsistency in findings has led to the conclusion that lipids stored within muscle cells are not always harmful to the cell (46).”
BackgroundZhang, J., Light, A. R., Hoppel, C. L., Campbell, C., Chandler, C. J., Burnett, D. J., de Souza, E. C. L., Casazza, G. A., Hughen, R. W., Keim, N. L., et al. (2016) · Experimental Physiology · doi:10.1113/ep086019 · Cited by 59 · see citing works
“In addition to elevations in acylcarnitine accumulation, the lipotoxicity of insulin resistance and T2DM can involve a higher muscle content of diacylglycerol and ceramides, both of which are implicated in inhibition of insulin signalling (reviewed by Coen & Goodpaster, 2012).”
BackgroundGemmink, A., Bosma, M., Kuijpers, H., Hoeks, J., Schaart, G., van Zandvoort, M., Schrauwen, P., & Hesselink, M. (2016) · Diabetologia · doi:10.1007/s00125-016-3865-z · Cited by 54 · see citing works
Singh, M., Kaur, R., Lee, M., Pickering, R. T., Sharma, V. M., Puri, V., & Kandror, K. V. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.c114.563080 · Cited by 58 · see citing works
Subsarcolemmal lipid droplet responses to a combined endurance and strength exercise intervention
Li, Y.-C., Lee, S., Langleite, T., Norheim, F., Pourteymour, S., Jensen, J., Stadheim, H. K., Storås, T., Davanger, S., Gulseth, H., et al. (2014) · Physiological Reports · doi:10.14814/phy2.12187 · Cited by 51 · see citing works
Central fat and peripheral muscle: partners in crime in chronic obstructive pulmonary disease.
van den Borst, B., Gosker, H., & Schols, A. (2013) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201208-1441oe · Cited by 50 · see citing works
“Metabolic inflexibility may lead to the accumulation of intramyocellular lipids, which has been associated with insulin resistance through mechanisms possibly involving the lipid intermediates ceramides and diacylglycerol, which interfere with insulin signaling pathways (19).”
BackgroundSex-based differences in hepatic and skeletal muscle triglyceride storage and metabolism.
Beaudry, K. M., & Devries, M. (2019) · Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme · doi:10.1139/apnm-2018-0635 · Cited by 49 · see citing works
“…paradox”, where highly IS, endurance athletes have a similar IMCL content as IR, obese and type 2 diabetic (T2D) individuals (Dube et al. 2008; Coen and Goodpaster 2012; Daemen et al. 2018) is an active area of research with recent evidence suggesting that it is not IMCL content per se…”
BackgroundLipid signals and insulin resistance
Zhang, C.-B., Klett, E., & Coleman, R. (2013) · Clinical Lipidology · doi:10.2217/clp.13.67 · Cited by 49 · see citing works
Physical Activity and Diet in Older Women: A Narrative Review
Mattioli, A., Selleri, V., Zanini, G., Nasi, M., Pinti, M., Stefanelli, C., Fedele, F., & Gallina, S. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm12010081 · Cited by 48 · see citing works
“Fat redistribution is reflected in the presence of intermuscular adipose tissue (IMAT) [39,40].”
BackgroundCholesterol—The Devil You Know; Ceramide—The Devil You Don’t
Tippetts, T. S., Holland, W., & Summers, S. (2021) · TIPS - Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.10.001 · Cited by 47 · see citing works
Alcoholic and non-alcoholic fatty liver disease: Focus on ceramide.
Nikolova-Karakashian, M. (2018) · Advances in Biological Regulation · doi:10.1016/j.jbior.2018.11.004 · Cited by 46 · see citing works
Marín-Royo, G., Gallardo, I., Martínez-Martínez, E., Gutiérrez, B., Jurado-López, R., López-Andrés, N., Gutiérrez-Tenorio, J., Rial, E., Bartolomé, M., Nieto, M., et al. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.032086 · Cited by 45 · see citing works
“These data confirm previous observations that found no link between either TG or LPC circulating levels and insulin resistance in the context of obesity (Coen and Goodpaster, 2012; del Bas et al., 2016; Eisinger et al., 2014; Tulipani et al., 2016).”
ResultThankamony, A., Capalbo, D., Marcovecchio, M., Sleigh, A., Jørgensen, S. W., Hill, N., Mooslehner, K., Yeo, G., Bluck, L., Juul, A., et al. (2014) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2013-4542 · Cited by 45 · see citing works
“Increased IMCLs in obesity and T2D is associated with reduced IS and is proposed to result from defective fat utilization related to impaired mitochondrial function (36).”
BackgroundFeng, Y. Z., Lund, J., Li, Y.-C., Knabenes, I. K., Bakke, S. S., Kase, E. T., Lee, Y., Kimmel, A. R., Thoresen, G. H., Rustan, A., et al. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m079764 · Cited by 44 · see citing works
“TAG lipolysis, rather than lipid content per se (12).”
BackgroundThankam, F., Dilisio, M. F., & Agrawal, D. (2016) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-016-2710-5 · Cited by 44 · see citing works
Bhullar, A., Añoveros-Barrera, A., Dunichand-Hoedl, A., Martins, K. J. B., Bigam, D., Khadaroo, R., McMullen, T., Bathe, O., Putman, C. T., Clandinin, M., et al. (2020) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12533 · Cited by 42 · see citing works
“insulin resistance, inflammation, and functional deficit in skeletal muscle.(38,39) EMCL can originate from adipogenic differentiation of stem cell populations of skeletal muscle.”
BackgroundHeo, J.-W., Yoo, S., No, M.-H., Park, D.-H., Kang, J.-H., Kim, T.-W., Kim, C.-J., Seo, D., Han, J., Yoon, J.-H., et al. (2018) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph15102301 · Cited by 42 · see citing works
Plasma lipid profiling of tissue-specific insulin resistance in human obesity
van der Kolk, B. W., Vogelzangs, N., Jocken, J. W. E., Valsesia, A., Hankemeier, T., Astrup, A. V., Saris, W. H. M., Arts, I. C. W., van Greevenbroek, M. M. J., & Blaak, E. E. (2018) · International Journal of Obesity · doi:10.1038/s41366-018-0189-8 · Cited by 60 · see citing works
The role of mTOR in lipid homeostasis and diabetes progression
Chakrabarti, P., & Kandror, K. V. (2015) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000187 · Cited by 43 · see citing works
“up’ ATGL products, such as DAG and FFA, that are thought to represent ‘real’ inducers of insulin resistance unlike chemically inert triglycerides [66,70,74,92].”
BackgroundCrescenzo, R., Bianco, F., Coppola, P., Mazzoli, A., Cigliano, L., Liverini, G., & Iossa, S. (2013) · British Journal Of Nutrition · doi:10.1017/s0007114513001566 · Cited by 42 · see citing works
“This result is in agreement with increased skeletal muscle ceramide content, since it is well known that ceramide has been identified as a key mediator of insulin resistance via inhibition of Akt phosphorylation((30)), and indicates that insulin action is blunted in skeletal muscle from fructose-fed rats.”
Jacobs, R., Díaz, V., Soldini, L., Haider, T., Thomassen, M., Nordsborg, N., Gassmann, M., & Lundby, C. (2013) · The journals of gerontology. Series A, Biological sciences and medical sciences · doi:10.1093/gerona/gls335 · Cited by 41 · see citing works
Sugimoto, D., Tamura, Y., Takeno, K., Kaga, H., Someya, Y., Kakehi, S., Funayama, T., Furukawa, Y., Suzuki, R., Kadowaki, S., et al. (2019) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2018-02190 · Cited by 39 · see citing works
Skeletal Muscle Fat and Its Association With Physical Function in Rheumatoid Arthritis
Khoja, S. S., Moore, C. G., Goodpaster, B. H., Delitto, A., & Piva, S. R. (2017) · Arthritis Care & Research · doi:10.1002/acr.23278 · Cited by 47 · see citing works
“Although not directly studied, it has been postulated that fat encroachment within the skeletal muscle can affect the contractile, neuromuscular, and metabolic functions by altering the muscle’s extracellular matrix and connective tissue properties (9), and through the release of toxic lipid byproducts (8).”
BackgroundSelf-citationAlvehus, M., Boman, N., Söderlund, K., Svensson, M., & Burén, J. (2014) · European Journal of Applied Physiology · doi:10.1007/s00421-014-2879-9 · Cited by 39 · see citing works
Bucher, J., Krüsi, M., Zueger, T., Ith, M., Stettler, C., Diem, P., Boesch, C., Kreis, R., & Christ, E. (2014) · Diabetologia · doi:10.1007/s00125-014-3193-0 · Cited by 39 · see citing works
“The consequences of increased ectopic lipids are dual: (1) they may alter organ function directly (lipotoxicity); and (2) metabolites of ectopic lipids may be involved in mediating insulin sensitivity [2].”
BackgroundResultInfluentialWang, L., Zhao, X.-Y., Liu, S., You, W.-J., Huang, Y., Zhou, Y., Chen, W., Zhang, S., Wang, J.-Y., Zheng, Q., et al. (2023) · npj Science of Food · doi:10.1038/s41538-023-00203-4 · Cited by 38 · see citing works
Impact of Dysfunctional Adipose Tissue Depots on the Cardiovascular System
D'Oria, R., Genchi, V. A., Caccioppoli, C., Calderoni, I., Marrano, N., Biondi, G., Borrelli, A., Gioia, L. D., Giorgino, F., & Laviola, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232214296 · Cited by 38 · see citing works
Skeletal muscle ceramide species in men with abdominal obesity
de la Maza, M., Rodríguez, J., Hirsch, S., Leiva, L., Barrera, G., & Bunout, D. (2014) · The Journal of Nutrition, Health & Aging · doi:10.1007/s12603-014-0548-7 · Cited by 38 · see citing works
“Furthermore, we did not find any association between muscle CER species and oxidative injury, as hypothesized to occur in response to CER-induced NFκB signaling (44).”
Dietary palmitate and oleate differently modulate insulin sensitivity in human skeletal muscle
Sarabhai, T., Koliaki, C. C., Mastrototaro, L., KAHL, S., Pesta, D. H., Apostolopoulou, M., Wolkersdorfer, M. F., Bönner, A. C., Bobrov, P., Markgraf, D. F., et al. (2021) · Diabetologia · doi:10.1007/s00125-021-05596-z · Cited by 42 · see citing works
“at least under conditions of a single oral lipid load [42].”
Backgroundde Almeida, A. C., Aily, J., Pedroso, M., Gonçalves, G., Felinto, J. D. C., Ferrari, R., Pastre, C. M., & Mattiello, S. (2019) · Clinical Rheumatology · doi:10.1007/s10067-019-04892-9 · Cited by 37 · see citing works
“This culminates in a lipotoxicity process [8] that may negatively contribute to force production and, consequently affect functional physical performance.”
BackgroundDubé, J. J., Sitnick, M., Schoiswohl, G., Wills, R. C., Basantani, M. K., Cai, L., Pulinilkunnil, T., & Kershaw, E. (2015) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00530.2014 · Cited by 37 · see citing works
Kase, E. T., Feng, Y. Z., Badin, P.-M., Bakke, S. S., Laurens, C., Coue, M., Langin, D., Gaster, M., Thoresen, G. H., Rustan, A. C., et al. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2015.03.005 · Cited by 36 · see citing works
Space Omics and Tissue Response in Astronaut Skeletal Muscle after Short and Long Duration Missions
Blottner, D., Moriggi, M., Trautmann, G., Hastermann, M., Capitanio, D., Torretta, E., Block, K., Rittweger, J., Limper, U., Gelfi, C., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24044095 · Cited by 36 · see citing works
“Impaired lipid oxidation induced ectopic fat deposition and lipotoxicity in human skeletal muscle [35] are both hallmarks in sarcopenia [36], whereas exercise promotes a change in anabolic pathways, such as muscular protein synthesis and lipid metabolism, also known as metabolic fueling (via lipid droplets), during ph…”
BackgroundSparks, L. M., Goodpaster, B. H., & Bergman, B. C. (2021) · Diabetes · doi:10.2337/dbi19-0006 · Cited by 35 · see citing works
Self-citationTowards Single Organelle Lipidomics in Live Cells
Lita, A., Kuzmin, A., Pliss, A., Baev, A., Rzhevskii, A., Gilbert, M., Larion, M., & Prasad, P. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b02663 · Cited by 34 · see citing works
Jheng, H.-F., Huang, S.-H., Kuo, H.-M., Hughes, M. W., & Tsai, Y. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12863 · Cited by 34 · see citing works
Savini, I., Gasperi, V., & Catani, M. (2016) · Springer eBooks · doi:10.1007/978-3-319-19821-7_6 · Cited by 34 · see citing works
Fabbri, E., Yang, A., Simonsick, E., Chia, C. W., Zoli, M., Haughey, N., Mielke, M., Ferrucci, L., & Coen, P. M. (2016) · Aging Cell · doi:10.1111/acel.12491 · Cited by 33 · see citing works
“Individuals with lower VO2 peak were more likely to be older, to weigh more, to be less active, to have higher systolic blood pressure, and to be affected by diabetes compared to those with higher VO2 peak (Table S2).”
BackgroundSelf-citationMikłosz, A., Lukaszuk, B., Baranowski, M., Górski, J., & Chabowski, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0085547 · Cited by 33 · see citing works
“Indeed, a number of independent studies have demonstrated that blocking ceramide accumulation using myriocin, cycloserine, or fumonisin B1 restores insulin-stimulated Akt and GSK3β phosphorylation, even in the presence of excess palmitate [20,37,43].”
BackgroundThe Pathological Links between Adiposity and the Carpal Tunnel Syndrome
Oțelea, M. R., Nartea, R., Popescu, F. G., Covaleov, A., Mitoiu, B. I., & Nica, A. S. (2022) · Current Issues in Molecular Biology · doi:10.3390/cimb44060181 · Cited by 39 · see citing works
“The intramyocellular lipids were found both in highly trained athletes and in insulin resistance patients, therefore their significance is interpreted in context: they might represent an extra fuel to comply with the higher needs or abnormal high storage contributing to the development of muscle insulin resistance [25…”
BackgroundGülen, M., Bagla, A. G., Yavuz, O., & Hismiogullari, A. (2015) · Biotechnic & Histochemistry · doi:10.3109/10520295.2015.1021380 · Cited by 32 · see citing works
“It now is clear that intramyocellular accumulation of the lipid metabolites, ceramide and diacylglycerol, is associated with the development of IR (Coen and Goodpaster 2012).”
BackgroundXu, F., Cao, H., Chen, Z., Gu, H., Guo, W., Lin, B., & Weng, J. (2020) · International Journal of Obesity · doi:10.1038/s41366-019-0513-y · Cited by 31 · see citing works
- Authors
- Coen, P. M., & Goodpaster, B. H.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Goodpaster, Bret H.
- Venue
- Trends in Endocrinology & Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 23
- Issue
- 8
- Pages
- 391-398
- ISSN
- 1043-2760 (ISSN-L)
- PMC
- PMC4908975
- OpenAlex
- W2017044391
- Cited by
- 252
- References
- 100
- Citations by year
- 2026: 17 · 2025: 13 · 2024: 11 · 2023: 13 · 2022: 16 · 2021: 13 · 2020: 14 · 2019: 18 · 2018: 23 · 2017: 18 · 2016: 24 · 2015: 25 · 2014: 23 · 2013: 24
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG021961, P30AG024827)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- intramyocellular lipid, intramuscular triglycerides, lipid droplets, muscle insulin resistance, type 2 diabetes, ceramide, diacylglycerol, lipid droplet proteins, lipidomics, proteomics
- MeSH terms
- Animals, Biological Transport, Ceramides, Diabetes Mellitus, Type 2, Diglycerides, Energy Metabolism, Fatty Acids, Humans, Insulin Resistance, Lipids, Mitochondria, Muscle, Triglycerides, Organelles, Exercise, Muscle, Skeletal, Muscle Cells, Lipid Metabolism
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