The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-α
Abstract
IL-6 and TNF-alpha have been associated with insulin resistance and type 2 diabetes. Furthermore, abnormalities in muscle fatty acid (FA) metabolism are strongly associated with the development of insulin resistance. However, few studies have directly examined the effects of either IL-6 or TNF-alpha on skeletal muscle FA metabolism. Here, we used a pulse-chase technique to determine the effect of IL-6 (50-5,000 pg/ml) and TNF-alpha (50-5,000 pg/ml) on FA metabolism in isolated rat soleus muscle. IL-6 (5,000 pg/ml) increased exogenous and endogenous FA oxidation by approximately 50% (P < 0.05) but had no effect on FA uptake or incorporation of FA into endogenous lipid pools. In contrast, TNF-alpha had no effect on FA oxidation but increased FA incorporation into diacylglycerol (DAG) by 45% (P < 0.05). When both IL-6 (5,000 pg/ml) and insulin (10 mU/ml) were present, IL-6 attenuated insulin's suppressive effect on FA oxidation, increasing exogenous FA oxidation (+37%, P < 0.05). Furthermore, in the presence of insulin, IL-6 reduced the esterification of FA to triacylglycerol by 22% (P < 0.05). When added in combination with IL-6 or leptin (10 microg/ml), the TNF-alpha-induced increase in DAG synthesis was inhibited. In conclusion, the results demonstrate that IL-6 plays an important role in regulating fat metabolism in muscle, increasing rates of FA oxidation, and attenuating insulin's lipogenic effects. In contrast, TNF-alpha had no effect on FA oxidation but increased FA incorporation into DAG, which may be involved in the development of TNF-alpha-induced insulin resistance in skeletal muscle.
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“and causes hepatic and muscle insulin resistance in humans and in mice (39,55-60).”
From Expression of Mfn2, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle (2005) · cites this paper as [56]
In the citing paper
“Several other studies have described that IL-6 can increase intramyocellular (58-60) or whole body (61) fatty acid oxidation via AMPK activation (58, 62).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [59]
In the citing paper
“Of note, whereas it is known that both TNF-α and IL-6 induce lipolysis [40, 49], only IL-6 appears to induce fat oxidation [19, 59].”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [59]
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Cites
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“Indeed, adiponectin and leptin stimulate FA oxidation (22, 37) and glucose uptake (15, 37) and prevent the accumulation of lipid in muscle (32, 38).”
BackgroundParadoxical Decrease of an Adipose-Specific Protein, Adiponectin, in Obesity
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“Decreased levels of adiponectin coincide with insulin resistance in obese/diabetic mice (4) and humans (2), and the development of peripheral leptin resistance occurs in fat-fed rats (33) and obese humans (34).”
BackgroundYamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., Ueki, K., et al. (2002) · Nature Medicine · doi:10.1038/nm788 · Cited by 4,238 · cited 2×
“Other adipocytokines that stimulate FA oxidation, such as adiponectin (37) and leptin (21), phosphorylate and activate the 2-catalytic subunit of AMPK (AMPK- 2) in skeletal muscle, suggesting that AMPK is a mediator of adiponectin and leptin’s effects on FA metabolism in muscle.”
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“Insulin resistance has been associated with elevated levels of plasma TNF- (41), and its expression is increased in adipose tissue (11) and skeletal muscle of insulin-resistant humans (25).”
BackgroundA central role for JNK in obesity and insulin resistance
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“In addition there is evidence that increased lipid availability may also cause insulin resistance by activating other serine/threonine kinases, including the inhibitor B protein kinases in the NF- B pathway (14) and the c-Jun NH2-terminal kinases [JNK (10)].”
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“TNF- may induce insulin resistance by inhibiting the activation of insulin receptor substrate (IRS)-1 (13) and by elevating plasma free fatty acids via stimulation of adipose tissue lipolysis (9).”
BackgroundLeptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase
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“Other adipocytokines that stimulate FA oxidation, such as adiponectin (37) and leptin (21), phosphorylate and activate the 2-catalytic subunit of AMPK (AMPK- 2) in skeletal muscle, suggesting that AMPK is a mediator of adiponectin and leptin’s effects on FA metabolism in muscle.”
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“DAG is a potent activator of some protein kinase C (PKC) isoforms [ II, , and (14, 27)], which may interfere with insulin signal transduction, particularly via serine phosphorylation of IRS-1 (39).”
BackgroundItani, S. I., Ruderman, N. B., Schmieder, F., & Boden, G. (2002) · Diabetes · doi:10.2337/diabetes.51.7.2005 · Cited by 1,390 · cited 3×
“In addition there is evidence that increased lipid availability may also cause insulin resistance by activating other serine/threonine kinases, including the inhibitor B protein kinases in the NF- B pathway (14) and the c-Jun NH2-terminal kinases [JNK (10)].”
BackgroundSkeletal 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
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Petersen, A. M. W., & Pedersen, B. K. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00164.2004 · Cited by 3,100
Muscles, exercise and obesity: skeletal muscle as a secretory organ
Pedersen, B. K., & Febbraio, M. A. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.49 · Cited by 2,909
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Pedersen, B. K., & Febbraio, M. A. (2008) · Physiological Reviews · doi:10.1152/physrev.90100.2007 · Cited by 2,388
“Apart from the effects of IL-6 on glucose metabolism, several studies have reported that IL-6 can increase intramyocellular (37, 53, 278) or whole body (372) fatty acid oxidation.”
BackgroundMechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294
“…(e.g., lipolysis from subcutaneous adipose tissue could have occurred, rates of lipid oxidation are dependent on numerous assumptions, etc.), it does recapitulate earlier studies demonstrating that IL-6 was capable of increasing lipid oxidation in isolated rat soleus (Bruce and Dyck, 2004).”
Steinberg, G. R., & Kemp, B. E. (2009) · Physiological Reviews · doi:10.1152/physrev.00011.2008 · Cited by 1,672
“Since the constitutively active AMPK fragment 1 (1-312) is not activated by the PT1 compound, it is proposed that PT1 acts by reversing the autoinhibition of the AIS (313-335).”
BackgroundInfluential
Metadata
- Authors
- Bruce, C. R., & Dyck, D. J.
- Affiliations
- University of Guelph (CA)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2004-10
- Volume
- 287
- Issue
- 4
- Pages
- E616-E621
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2128600629
- Cited by
- 178
- References
- 43
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 11 · 2022: 4 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 9 · 2015: 8 · 2014: 7 · 2013: 13 · 2012: 15
- FWCI
- 8.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- interleukin-6, TNF-α, skeletal muscle, fatty acid metabolism, fatty acid oxidation, insulin resistance, type 2 diabetes, diacylglycerol synthesis, triacylglycerol esterification, leptin, soleus muscle, lipogenesis
- MeSH terms
- Animals, Diglycerides, Fatty Acids, Female, Insulin Resistance, Kinetics, Oxidation-Reduction, Palmitates, Triglycerides, Tumor Necrosis Factor-alpha, Interleukin-6, Cytokines, Rats, Sprague-Dawley, Muscle, Skeletal, Leptin, Rats, In Vitro Techniques
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