Saturated Fatty Acid-Induced Endoplasmic Reticulum Stress and Insulin Resistance Are Prevented by Imoxin in C2C12 Myotubes
In obesity, plasma free fatty acids (FFAs) levels are elevated due to enlarged adipose tissue mass. Saturated fatty acids can induce prolonged ER stress and insulin resistance. Double-stranded RNA-dependent Protein Kinase (PKR) is activated under stress conditions in skeletal muscle. The current stu...
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| Format: | Article |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.842819/full |
| _version_ | 1811288635457142784 |
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| author | Hyeyoon Eo Hyeyoon Eo Rudy J Valentine Rudy J Valentine |
| author_facet | Hyeyoon Eo Hyeyoon Eo Rudy J Valentine Rudy J Valentine |
| author_sort | Hyeyoon Eo |
| collection | DOAJ |
| description | In obesity, plasma free fatty acids (FFAs) levels are elevated due to enlarged adipose tissue mass. Saturated fatty acids can induce prolonged ER stress and insulin resistance. Double-stranded RNA-dependent Protein Kinase (PKR) is activated under stress conditions in skeletal muscle. The current study aimed to investigate the effect of imoxin (IMX), a selective PKR inhibitor, on palmitate-induced ER stress and insulin resistance in C2C12 myotubes. Cells were treated with 5 μM imoxin and exposed to 0.5 mM bovine serum albumin (BSA)-conjugated PA for 24 h. A subset of cells was stimulated with 50 nM insulin for the last 15 min. Glucose uptake was monitored and protein levels involved in ER stress and insulin signaling were measured by Western blotting. Palmitate stimulated PKR phosphorylation, which was prevented by imoxin. Moreover, imoxin reduced protein levels of ER stress-related markers including glucose-regulating protein 78 (GRP78), CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6) and spliced X-box binding protein 1 (XBP-1s) which were induced by palmitate. Furthermore, imoxin ameliorated palmitate-induced suppression of phospho-insulin receptor beta (p-IRβ) and Akt phosphorylation in myotubes. In addition, imoxin promoted glucose uptake in response to insulin under palmitate exposure. Furthermore, imoxin reduced phospho-c-Jun N-terminal kinase (p-JNK) induced by palmitate treatment. These findings suggest that imoxin may protect against saturated fatty acid-induced ER stress and insulin resistance in skeletal muscle, which are potentially mediated by PKR. |
| first_indexed | 2024-04-13T03:40:47Z |
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| id | doaj.art-e0dc1df875a042b495d94801de94211f |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-13T03:40:47Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Physiology |
| spelling | doaj.art-e0dc1df875a042b495d94801de94211f2022-12-22T03:04:11ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-07-011310.3389/fphys.2022.842819842819Saturated Fatty Acid-Induced Endoplasmic Reticulum Stress and Insulin Resistance Are Prevented by Imoxin in C2C12 MyotubesHyeyoon Eo0Hyeyoon Eo1Rudy J Valentine2Rudy J Valentine3Department of Kinesiology, Iowa State University, Ames, IA, United StatesInterdepartmental Graduate Program in Nutritional Sciences, Iowa State University, Ames, IA, United StatesDepartment of Kinesiology, Iowa State University, Ames, IA, United StatesInterdepartmental Graduate Program in Nutritional Sciences, Iowa State University, Ames, IA, United StatesIn obesity, plasma free fatty acids (FFAs) levels are elevated due to enlarged adipose tissue mass. Saturated fatty acids can induce prolonged ER stress and insulin resistance. Double-stranded RNA-dependent Protein Kinase (PKR) is activated under stress conditions in skeletal muscle. The current study aimed to investigate the effect of imoxin (IMX), a selective PKR inhibitor, on palmitate-induced ER stress and insulin resistance in C2C12 myotubes. Cells were treated with 5 μM imoxin and exposed to 0.5 mM bovine serum albumin (BSA)-conjugated PA for 24 h. A subset of cells was stimulated with 50 nM insulin for the last 15 min. Glucose uptake was monitored and protein levels involved in ER stress and insulin signaling were measured by Western blotting. Palmitate stimulated PKR phosphorylation, which was prevented by imoxin. Moreover, imoxin reduced protein levels of ER stress-related markers including glucose-regulating protein 78 (GRP78), CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6) and spliced X-box binding protein 1 (XBP-1s) which were induced by palmitate. Furthermore, imoxin ameliorated palmitate-induced suppression of phospho-insulin receptor beta (p-IRβ) and Akt phosphorylation in myotubes. In addition, imoxin promoted glucose uptake in response to insulin under palmitate exposure. Furthermore, imoxin reduced phospho-c-Jun N-terminal kinase (p-JNK) induced by palmitate treatment. These findings suggest that imoxin may protect against saturated fatty acid-induced ER stress and insulin resistance in skeletal muscle, which are potentially mediated by PKR.https://www.frontiersin.org/articles/10.3389/fphys.2022.842819/fullimoxinPKRpalmitateER stressinsulin signaling |
| spellingShingle | Hyeyoon Eo Hyeyoon Eo Rudy J Valentine Rudy J Valentine Saturated Fatty Acid-Induced Endoplasmic Reticulum Stress and Insulin Resistance Are Prevented by Imoxin in C2C12 Myotubes Frontiers in Physiology imoxin PKR palmitate ER stress insulin signaling |
| title | Saturated Fatty Acid-Induced Endoplasmic Reticulum Stress and Insulin Resistance Are Prevented by Imoxin in C2C12 Myotubes |
| title_full | Saturated Fatty Acid-Induced Endoplasmic Reticulum Stress and Insulin Resistance Are Prevented by Imoxin in C2C12 Myotubes |
| title_fullStr | Saturated Fatty Acid-Induced Endoplasmic Reticulum Stress and Insulin Resistance Are Prevented by Imoxin in C2C12 Myotubes |
| title_full_unstemmed | Saturated Fatty Acid-Induced Endoplasmic Reticulum Stress and Insulin Resistance Are Prevented by Imoxin in C2C12 Myotubes |
| title_short | Saturated Fatty Acid-Induced Endoplasmic Reticulum Stress and Insulin Resistance Are Prevented by Imoxin in C2C12 Myotubes |
| title_sort | saturated fatty acid induced endoplasmic reticulum stress and insulin resistance are prevented by imoxin in c2c12 myotubes |
| topic | imoxin PKR palmitate ER stress insulin signaling |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.842819/full |
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