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Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway
Abstract
Background/objectives It has been reported that irisin regulated exercise-mediated adipocyte browning; however, the systematical effects of irisin on the metabolism of glucose and lipid in diabetes are largely unknown. In the present study, we investigated the role and underlying mechanism of irisin in glucose utilization and lipid metabolism in diabetic mice.Methods A mouse model of diabetes was established by feeding C57BL/6 mice with high-fat diet. The diabetic mice were then treated with irisin. To mimic type 2 diabetes in vitro, myocytes and hepatocytes were cultured in a medium of high glucose and high fat. Glucose uptake, fatty acid oxidation and the expression of related protein were evaluated.Results Irisin improved glucose tolerance and glucose uptake as evidenced by increased (18)F-FDG accumulation and GLUT4 translocation in diabetic skeletal muscle. Irisin also increased glucose uptake in myocytes cultured in high glucose/high fatty acid medium. In contrast, irisin reduced the expression of PEPCK and G6Pase, which are involved in gluconeogenesis, in diabetic liver. Consistently, irisin reduced fat weight and serum total cholesterol and triglyceride levels in diabetic mice, but increased acetyl coenzyme A carboxylase-β phosphorylation in muscle tissue and uncoupling protein 1 expression in fat tissue. In addition, irisin increased the oxidation of fatty acid in myocytes. Knockdown of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) attenuated the effects of irisin on glucose uptake and fatty acid β-oxidation in myocytes. Similarly, inhibition of AMPK by a specific inhibitor reduced the effects of irisin on PEPCK and G6Pase expression in hepatocytes.Conclusions Our results suggest that irisin has an essential role in glucose utilization and lipid metabolism, and irisin is a promising pharmacological target for the treatment of diabetes and its complications.
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“In SkM, after physical activity, irisin induced downstream activation of glucose and FFA uptake and oxidation [62].”
In the citing paper
“Exercise-inducible myokines, such as irisin [62,63], IL-6 [76,77], IL-15 [91,126], BAIBA [111], and METRNL [100], as well as the osteokine OCN [71] have been shown to directly stimulate oxidative metabolism in autocrine and endocrine ways, respectively (1).”
In the citing paper
“Other studies have reported effects of irisin on body fat reduction through other mechanisms, such as improved glucose tolerance and lipid oxidation via phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA-carboxylase [52, 53].”
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“In vivo, administration of irisin to high-fat diet (HFD)-fed mice decreased the fasting blood glucose level, and improved glucose and insulin tolerance; the same effects were detected in obese and HFD-fed mice with FNDC5 overexpression [95].”
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“Similarly, the enhanced uptake of glucose in the C2C12 cells treated with irisin and cultured in high ambient glucose and PA containing medium were alleviated after the inhibition of the AMPK signaling with AMPKα2 siRNA [62].”
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“Collectively, the findings provide the explanation for the increased oxidative stress and neuronal apoptosis under high glucose conditions (Fossati et al., 2016; Xu et al., 2016).”
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Pang, Y., Zhu, H., Xu, J., Yang, L., Liu, L., & Li, J. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.09.006 · Cited by 46
Kolodziejski, P. A., Pruszyńska‐Oszmałek, E., Wojciechowicz, T., Sassek, M., Leciejewska, N., Jasaszwili, M., Billert, M., Małek, E., Szczepankiewicz, D., Misiewicz-Mielnik, M., et al. (2021) · Genes · doi:10.3390/genes12050756 · Cited by 46
“It was shown that irisin increases fatty acid β-oxidation in muscle tissue [77].”
BackgroundWu, X., Li, X., Dang, Z., & Jia, Y. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26681 · Cited by 42
“pylori-infected mice with chronic gastritis mice was established, as described previously.(18,19) Briefly, male C57Bl/6 mice (4 weeks old, 19-21 g) were purchased from Henan Province Hospital of TCM.”
MethodLi, L., Wang, Y., Zeng, X., Hu, Y. M., Zhang, J., Wang, B., & Chen, S. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.136186 · Cited by 41
The role of irisin in metabolic flexibility: Beyond adipose tissue browning
Shen, S., Liao, Q., Chen, X., Peng, C. Y., & Lin, L. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.03.019 · Cited by 42
Yang, X.-Y., Tse, M. C. L., Hu, X., Jia, W.-H., Du, G., & Chan, C. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000494655 · Cited by 33
Irisin at the crossroads of inter-organ communications: Challenge and implications
Zhao, R. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.989135 · Cited by 40
“Additionally, in diabetic obese C57BL/6 mice, the injection of r-irisin (0.5 µg/g body weight) caused a reduction in Pepck and G6pase expressions in the liver by stimulating the AMPK signaling pathway, and blocking of AMPK signaling decreased the influence of irisin on hepatocytic expressions of Pepck and G6pase (86).”
BackgroundInfluentialIrisin is a biomarker for metabolic syndrome in prepubertal children
Shim, Y. S., Kang, M. J., Yang, S., & Hwang, I. T. (2017) · Endocrine Journal · doi:10.1507/endocrj.ej17-0260 · Cited by 37
Juszczak, F., Vlassembrouck, M., Botton, O., Zwakhals, T., Decarnoncle, M., Tassin, A., Caron, N., & Declèves, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010350 · Cited by 35
“Interestingly, inhibition of AMPK by a specific inhibitor reduced the effects of Irisin in myocytes and hepatocytes, suggesting that Irisin could be implicated in AMPK pathway regulation [72].”
BackgroundMechanism of CNS regulation by irisin, a multifunctional protein
Qi, J., Yang, L.-K., Wang, X., Wang, M., Li, X., Feng, B., Wu, Y., Liu, S., & Zhang, K. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.07.007 · Cited by 37
Llanos, P., & Palomero, J. (2022) · Cells · doi:10.3390/cells11244008 · Cited by 39
Irisin regulates cardiac physiology in zebrafish
Sundarrajan, L., Yeung, C., Hahn, L., Weber, L. P., & Unniappan, S. (2017) · PLoS ONE · doi:10.1371/journal.pone.0181461 · Cited by 35
Relation of serum irisin level with metabolic and antropometric parameters in obese children
Çatlı, G., Küme, T., Tuhan, H., Anık, A., Çalan, Ö. G., Böber, E., & Abacı, A. (2016) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2016.07.019 · Cited by 34
Increased FNDC5 is associated with insulin resistance in high fat‐fed mice
Guilford, B. L., Parson, J. C., Grote, C., Vick, S. N., Ryals, J. M., & Wright, D. (2017) · Physiological Reports · doi:10.14814/phy2.13319 · Cited by 35
“Our results are congruent with previous reports in both animals and humans that suggest the PGC-1aFNDC5/irisin pathway is upregulated in response to chronically elevated blood glucose as well as HOMA-IR (Huh et al. 2012; Kleiner et al. 2012; Crujeiras et al. 2014; Keuper et al. 2014; Yang et al. 2015; Xin et al. 2016;…”
BackgroundResultInfluentialLi, B., Yao, Q., Guo, S., Ma, S., Dong, Y., Xin, H., Wang, H., Liu, L., Chang, W., & Zhang, Y. (2018) · Clinical and Experimental Hypertension · doi:10.1080/10641963.2018.1529779 · Cited by 34
“(8) reported that Irisin ameliorates blood glucose homeostasis through aggrandizing fatty acid oxidation and exploiting glucose adopt by the AMPK signaling pathway in a study on diabetic mice.”
BackgroundKooshki, F., Tutunchi, H., Vajdi, M., Karimi, A., Niazkar, H. R., Shoorei, H., & Gargari, B. P. (2021) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13462 · Cited by 39
Adipose tissue in older individuals: a contributing factor to sarcopenia
Wang, T., Zhou, D., & Hong, Z. (2024) · Metabolism · doi:10.1016/j.metabol.2024.155998 · Cited by 37
Tsai, C., & Pai, M. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.113013 · Cited by 35
Amri, J., Parastesh, M., Sadegh, M., Latifi, S. A., & Alaee, M. (2019) · Physiology International · doi:10.1556/2060.106.2019.24 · Cited by 35
“(40) showed that injection of irisin in type 2 diabetes increased GLUT4 in skeletal muscle and decreased enzymes involved in the gluconeogenesis.”
BackgroundSerum irisin, adropin, and preptin in obese patients 6 months after bariatric surgery
Glück, M., Glück, J., Wiewióra, M., Rogala, B., & Piecuch, J. (2019) · Obesity Surgery · doi:10.1007/s11695-019-03998-y · Cited by 31
Pelczyńska, M., Miller‐Kasprzak, E., Piątkowski, M., Mazurek, R., Klause, M., Suchecka, A., Bucoń, M., & Bogdański, P. (2023) · Antioxidants · doi:10.3390/antiox12122046 · Cited by 37
Abdul-Rahman, O., Kristóf, E., Doan‐Xuan, Q., Vida, A., Nagy, L., Horváth, A., Simon, J., Maros, T., Szentkirályi, I., Palotás, L., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0157644 · Cited by 32
Babaei, P., Shirkouhi, S. G., Hoseini, R., & Tehrani, B. S. (2017) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-017-0288-z · Cited by 31
“Irisin has been proposed to be secreted by myocytes and adipocytes during exercise [17, 55] and modulates energy expenditure [17] insulin resistance [17] and dyslipidemia [56, 57].”
BackgroundWang, P., Ma, H.-H., Hou, X., Song, L., Song, X.-L., & Zhang, J.-F. (2018) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2018.05.038 · Cited by 31
Irisin and Energy Metabolism and the Role of Irisin on Metabolic Syndrome
Aladag, T., Moğulkoç, R., & Baltacı, A. K. (2023) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/1389557523666230411105506 · Cited by 30
Yen, C., Chang, P., Chang, Y., & Lin, P. (2022) · Antioxidants · doi:10.3390/antiox11040725 · Cited by 30
“Irisin assists in utilizing glucose and stimulates fatty acid oxidation in skeletal muscle tissue [10].”
BackgroundGuo, Q., Wei, X., Hu, H., Yang, D., Zhang, B., Fan, X., Liu, J., He, H., Oh, Y., Wu, Q., et al. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.10.077 · Cited by 30
Li, Y., Wang, B., Shen, J.-D., Bai, M., & Xu, E. (2020) · Pharmaceutical Biology · doi:10.1080/13880209.2020.1756349 · Cited by 32
“Therefore, the activation of AMPK has been proposed as an important target for improving insulin sensitivity (Kim et al. 2009; Xin et al. 2016).”
Background
Metadata
- Authors
- Xin, C., Liu, J., Zhang, J., Zhu, D., Wang, H., Xiong, L., Lee, Y., Ye, J., Lian, K., Xu, C., Zhang, L., Wang, Q., Liu, Y., & Tao, L.
- Affiliations
- Second Artillery General Hospital of Chinese People's Liberation Army (CN)
- Xijing Hospital (CN)
- Corresponding author
- Liu, Y
- Tao, L
- Venue
- International Journal of Obesity
- Published
- 2015-09-25
- Volume
- 40
- Issue
- 3
- Pages
- 443-451
- ISSN
- 0307-0565 (ISSN-L)
- 1476-5497
- OpenAlex
- W1923336662
- Cited by
- 248
- References
- 44
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 24 · 2023: 26 · 2022: 28 · 2021: 32 · 2020: 29 · 2019: 19 · 2018: 22 · 2017: 21 · 2016: 12 · 2015: 1
- FWCI
- 14.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Obesity (publishedVersion)
- PubMed (publishedVersion)
- 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 › Metabolism, Diabetes, and Cancer
- Keywords
- irisin, type 2 diabetes, AMPK signaling, fatty acid oxidation, glucose utilization, glucose uptake, GLUT4 translocation, skeletal muscle, gluconeogenesis, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, hepatic glucose metabolism, lipid metabolism, ACACB, UCP1, high-fat diet, glucose tolerance
- MeSH terms
- Animals, Blood Glucose, Diabetes Mellitus, Experimental, Disease Models, Animal, Fatty Acids, Fibronectins, Glucose, Male, Mice, Inbred C57BL, Oxidation-Reduction, Phosphorylation, Signal Transduction, Muscle, Skeletal, Lipid Metabolism, Glucose Transporter Type 4, Mice, AMP-Activated Protein Kinases
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