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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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“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]
In the citing paper
“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]
In the citing paper
“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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BackgroundSkeletal muscle insulin resistance: role of mitochondria and other ROS sources
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“…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).”
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BackgroundSkeletal Muscle Triacylglycerol Hydrolysis Does Not Influence Metabolic Complications of Obesity
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“Intramyocellular fat is not necessarily abnormal as it serves as an energy source to fuel muscle contraction.(8,20) The”
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“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).”
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“The inconsistency in findings has led to the conclusion that lipids stored within muscle cells are not always harmful to the cell (46).”
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“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. C. (2019) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2018-0635 · Cited by 69
“…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., Klett, E. L., & Coleman, R. (2013) · Clinical Lipidology · doi:10.2217/clp.13.67 · Cited by 58
Physical Activity and Diet in Older Women: A Narrative Review
Mattioli, A. V., 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 53
“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. L., & Summers, S. A. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.10.001 · Cited by 53
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 53
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
“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
“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., Lund, J., Li, Y., Knabenes, I. K., Bakke, S. S., Kase, E. T., Lee, Y. K., Kimmel, A. R., Thoresen, G. H., Rustan, A. C., et al. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m079764 · Cited by 51
“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
Bhullar, A. S., Anoveros‐Barrera, A., Dunichand‐Hoedl, A. R., Martins, K. J. B., Bigam, D. L., Khadaroo, R. G., McMullen, T. P. W., Bathe, O. F., Putman, C. T., Clandinin, M. T., et al. (2020) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12533 · Cited by 57
“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., Yoo, S.-Z., No, M., Park, D., Kang, J., Kim, T.-W., Kim, C., Seo, D. Y., Han, J., Yoon, J.-H., et al. (2018) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph15102301 · Cited by 44
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 61
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 44
“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
“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. A., Díaz, V., Soldini, L., Haider, T., Thomassen, M., Nordsborg, N. B., Gassmann, M., & Lundby, C. (2013) · The Journals of Gerontology Series A · doi:10.1093/gerona/gls335 · Cited by 37
Sugimoto, D., Tamura, Y., Takeno, K., Kaga, H., Someya, Y., Kakehi, S., Funayama, T., Furukawa, Y., Suzuki, R., Kadowaki, S., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-02190 · Cited by 43
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
“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
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
“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
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
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
“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
“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
“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
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
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
“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
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
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Fabbri, E., An, Y., Simonsick, E. M., Chia, C. W., Zoli, M., Haughey, N. J., Mielke, M. M., Ferrucci, L., & Coen, P. M. (2016) · Aging Cell · doi:10.1111/acel.12491 · Cited by 36
“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., Łukaszuk, B., Baranowski, M., Górski, J., & Chabowski, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0085547 · Cited by 33
“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
“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. İ., Bağla, A. G., Yavuz, Ö., & Hismiogullari, A. (2015) · Biotechnic & Histochemistry · doi:10.3109/10520295.2015.1021380 · Cited by 33
“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
Metadata
- 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 (medical) › 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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