Irisin ameliorates hepatic glucose/lipid metabolism and enhances cell survival in insulin-resistant human HepG2 cells through adenosine monophosphate-activated protein kinase signaling
Abstract
Irisin is a newly identified myokine that promotes the browning of white adipose tissue, enhances glucose uptake in skeletal muscle and modulates hepatic metabolism. However, the signaling pathways involved in the effects on hepatic glucose and lipid metabolism have not been resolved. This study aimed to examine the role of irisin in the regulation of hepatic glucose/lipid metabolism and cell survival, and whether adenosine monophosphate-activated protein kinase (AMPK), a master metabolic regulator in the liver, is involved in irisin's actions. Human liver-derived HepG2 cells were cultured in normal glucose-normal insulin (NGNI) or high glucose-high insulin (HGHI/insulin-resistant) condition. Hepatic glucose and lipid metabolism was evaluated by glucose output and glycogen content or triglyceride accumulation assays, respectively. Our results showed that irisin stimulated phosphorylation of AMPK and acetyl-CoA-carboxylase (ACC) via liver kinase B1 (LKB1) rather than Ca(2+)/calmodulin-dependent protein kinase kinase β (CaMKKβ) in HepG2 cells. Irisin ameliorated hepatic insulin resistance induced by HGHI condition. Irisin reduced hepatic triglyceride content and glucose output, but increased glycogen content, with those effects reversed by dorsomorphin, an AMPK inhibitor. Furthermore, irisin also stimulated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and promoted cell survival in an AMPK-dependent manner. In conclusion, our data indicate that irisin ameliorates dysregulation of hepatic glucose/lipid metabolism and cell death in insulin-resistant states via AMPK activation. These findings reveal a novel irisin-mediated protective mechanism in hepatic metabolism which provides a scientific basis for irisin as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes mellitus.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Other studies have reported effects of irisin on body fat reduction through mechanisms other than UCP-1, such as improved glucose tolerance and lipid oxidation via phosphorylation of AMPK and acetyl-CoA-carboxylase.
“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].”
Cites
1 retracted
Ferreira, D. M. S., Castro, R. E., Machado, M. V., Evangelista, T., Silvestre, A. R., Costa, A., Coutinho, J. R. H., Carepa, F., Cortez‐Pinto, H., & Rodrigues, C. M. P. (2011) · Diabetologia · doi:10.1007/s00125-011-2130-8 · Cited by 97 · see citing works
RetractedRole of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652 · see citing works
A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis
Boström, P., Wu, J., Jedrychowski, M. P., Korde, A., Ye, L., Lo, J. C., Rasbach, K. A., Boström, E. A., Choi, J. H., Long, J. Z., et al. (2012) · Nature · doi:10.1038/nature10777 · Cited by 4,810 · see citing works
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 · see citing works
Kahn, B. B., Alquier, T., Carling, D., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.003 · Cited by 2,799 · see citing works
Li, Y., Xu, S., Mihaylova, M. M., Zheng, B., Hou, X., Jiang, B., Park, O., Luo, Z., Lefai, É., Shyy, J. Y.-J., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.03.009 · Cited by 1,788 · see citing works
Mitogen-activated protein kinases in apoptosis regulation
Wada, T., & Penninger, J. M. (2004) · Oncogene · doi:10.1038/sj.onc.1207556 · Cited by 1,432 · see citing works
The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes
Perry, R. J., Samuel, V. T., Petersen, K. F., & Shulman, G. I. (2014) · Nature · doi:10.1038/nature13478 · Cited by 1,136 · see citing works
AMP-activated protein kinase signaling in metabolic regulation
Long, Y. C. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29044 · Cited by 1,097 · see citing works
Huh, J. Y., Panagiotou, G., Mougios, V., Brinkoetter, M., Vamvini, M. T., Schneider, B. E., & Mantzoros, C. S. (2012) · Metabolism · doi:10.1016/j.metabol.2012.09.002 · Cited by 1,040 · see citing works
Kulik, G., Klippel, A., & Weber, M. J. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.3.1595 · Cited by 1,033 · see citing works
The interaction of hepatic lipid and glucose metabolism in liver diseases
Bechmann, L. P., Hannivoort, R. A., Gerken, G., Hotamışlıgil, G. S., Trauner, M., & Canbay, A. E. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2011.08.025 · Cited by 992 · see citing works
Adiponectin and AdipoR1 Regulate PGC-1α and Mitochondria by Ca2+ and AMPK/SIRT1
Iwabu, M., Yamauchi, T., Okada-Iwabu, M., Sato, K., Nakagawa, T., Funata, M., Yamaguchi, M., Namiki, S., Nakayama, R., Tabata, M., et al. (2010) · Nature · doi:10.1038/nature08991 · Cited by 971 · see citing works
AMPK, insulin resistance, and the metabolic syndrome
Ruderman, N. B., Carling, D., Prentki, M., & Cacicedo, J. M. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67227 · Cited by 877 · see citing works
Salminen, A., Hyttinen, J. M. T., & Kaarniranta, K. (2011) · Journal of Molecular Medicine · doi:10.1007/s00109-011-0748-0 · Cited by 866 · see citing works
SIRT1 Regulates Hepatocyte Lipid Metabolism through Activating AMP-activated Protein Kinase
Hou, X., Xu, S., Maitland-Toolan, K. A., Sato, K., Jiang, B., Ido, Y., Lan, F., Walsh, K., Wierzbicki, M., Verbeuren, T. J., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802187200 · Cited by 778 · see citing works
Zhang, Y., Li, R., Meng, Y., Li, S., Donelan, W., Zhao, Y., Qi, L., Zhang, M., Wang, X., Cui, T., et al. (2014) · Diabetes · doi:10.2337/db13-1106 · Cited by 733 · see citing works
De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose
Sanders, F., & Griffin, J. L. (2015) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12178 · Cited by 543 · see citing works
Wu, X.-D., Motoshima, H., Mahadev, K., Stalker, T. J., Scalia, R., & Goldstein, B. (2003) · Diabetes · doi:10.2337/diabetes.52.6.1355 · Cited by 471 · see citing works
Zang, M., Zuccollo, A., Hou, X., Nagata, D., Walsh, K. X., Herscovitz, H., Brecher, P. I., Ruderman, N. B., & Cohen, R. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408149200 · Cited by 450 · see citing works
Lochhead, P. A., Salt, I. P., Walker, K. S., Hardie, D. G., & Sutherland, C. D. (2000) · Diabetes · doi:10.2337/diabetes.49.6.896 · Cited by 391 · see citing works
Insulin resistance in hepatocytes and sinusoidal liver cells: Mechanisms and consequences
Leclercq, I. A., Morais, A. D. S., Schroyen, B., Hul, N. V., & Geerts, A. E. (2007) · Journal of Hepatology · doi:10.1016/j.jhep.2007.04.002 · Cited by 359 · see citing works
Liu, T.-Y., Shi, C.-X., Gao, R., Sun, H.-J., Xiong, X.-Q., Ding, L., Chen, Q., Li, Y.-H., Wang, J.-J., Kang, Y.-M., et al. (2015) · Clinical science · doi:10.1042/cs20150009 · Cited by 352 · see citing works
Hepatocytes: critical for glucose homeostasis
Klover, P. J., & Mooney, R. A. (2003) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2003.10.002 · Cited by 345 · see citing works
High Glucose Causes Apoptosis in Cultured Human Pancreatic Islets of Langerhans
Federici, M., Hribal, M. L., Perego, L., Ranalli, M., Caradonna, Z., Perego, C., Usellini, L., Nano, R., Bonini, P., Bertuzzi, F., et al. (2001) · Diabetes · doi:10.2337/diabetes.50.6.1290 · Cited by 333 · see citing works
Dentin, R., Girard, J. R., & Postic, C. (2004) · Biochimie · doi:10.1016/j.biochi.2004.11.008 · Cited by 328 · see citing works
A Non-canonical MEK/ERK Signaling Pathway Regulates Autophagy via Regulating Beclin 1
Wang, J., Whiteman, M. W., Lian, H., Wang, G., Singh, A. K., Huang, D., & Denmark, T. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.026013 · Cited by 319 · see citing works
STO-609, a Specific Inhibitor of the Ca2+/Calmodulin-dependent Protein Kinase Kinase
Tokumitsu, H., Inuzuka, H., Ishikawa, Y., Ikeda, M., Saji, I., & Kobayashi, R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201075200 · Cited by 293 · see citing works
Qiao, X., Nie, Y., Ma, Y., Chen, Y., Cheng, R., Yin, W., Hu, Y., Xu, W., & Xu, L. (2016) · Scientific Reports · doi:10.1038/srep18732 · Cited by 291 · see citing works
Ho, F. M., Liu, S., Liau, C. S., Huang, P. J., & Lin‐Shiau, S. Y. (2000) · Circulation · doi:10.1161/01.cir.101.22.2618 · Cited by 288 · see citing works
Azzout‐Marniche, D., Bécard, D., Guichard, C., Foretz, M., Ferré, P., & Foufelle, F. (2000) · Biochemical Journal · doi:10.1042/bj3500389 · Cited by 257 · see citing works
Xin, C., Liu, J., Zhang, J., Zhu, D., Wang, H., Xiong, L., Lee, Y., Ye, J., Lian, K., Xu, C., et al. (2016) · International Journal of Obesity · doi:10.1038/ijo.2015.199 · Cited by 248 · see citing works
Xiong, X.-Q., Chen, D., Sun, H.-J., Ding, L., Wang, J.-J., Chen, Q., Li, Y.-H., Zhou, Y.-B., Han, Y., Zhang, F., et al. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.06.017 · Cited by 242 · see citing works
Irisin, a Novel Myokine, Regulates Glucose Uptake in Skeletal Muscle Cells via AMPK
Lee, H. J., Lee, J. O., Kim, N., Kim, J. K., Kim, H. I., Lee, Y. W., Kim, S. J., Choi, J., Oh, Y., Kim, J. H., et al. (2015) · Molecular Endocrinology · doi:10.1210/me.2014-1353 · Cited by 219 · see citing works
Lu, J., Xiang, G., Liu, M., Mei, W., Xiang, L., & Dong, J. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.10.020 · Cited by 190 · see citing works
Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway
Awazawa, M., Ueki, K., Inabe, K., Yamauchi, T., Kaneko, K., Okazaki, Y., Bardeesy, N. M., Ohnishi, S., Nagai, R., & Kadowaki, T. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.02.131 · Cited by 186 · see citing works
Kraemer, R. R., Shockett, P. E., Webb, N., Shah, U. R., & Castracane, V. D. (2013) · Hormone and Metabolic Research · doi:10.1055/s-0033-1355381 · Cited by 181 · see citing works
New role of irisin in hepatocytes: the protective effect of hepatic steatosis in vitro
Park, M.-J., Kim, D.-I., Choi, J.-H., Heo, Y.-R., & Park, S.-H. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.04.010 · Cited by 168 · see citing works
Cordero‐Herrera, I., Martín, M. Á., Goya, L., & Ramos, S. (2013) · Food and Chemical Toxicology · doi:10.1016/j.fct.2013.11.014 · Cited by 156 · see citing works
Phosphorylation of BRAF by AMPK Impairs BRAF-KSR1 Association and Cell Proliferation
Shen, C., Yuan, P., Pérez‐Lorenzo, R., Zhang, Y., Lee, S. X., Ou, Y., Asara, J. M., Cantley, L. C., & Zheng, B. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.08.044 · Cited by 132 · see citing works
Qiao, X., Nie, Y., Ma, Y., Chen, Y., Cheng, R., Yin, W., Hu, Y., Xu, W., & Xu, L. (2016) · Scientific Reports · doi:10.1038/srep21053 · Cited by 132 · see citing works
Irisin Is Elevated in Skeletal Muscle and Serum of Mice Immediately after Acute Exercise
Brenmoehl, J., Albrecht, E., Komolka, K., Schering, L., Langhammer, M., Hoeflich, A., & Maak, S. (2014) · International Journal of Biological Sciences · doi:10.7150/ijbs.7972 · Cited by 127 · see citing works
Nakajima, K., Yamauchi, K., Shigematsu, S., Ikeo, S., Komatsu, M., Aizawa, T., & Hashizume, K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m905410199 · Cited by 103 · see citing works
Mechanism of AMPK Suppression of LXR-dependent Srebp-1c Transcription
Yap, F. C., Craddock, L., & Yang, J. (2011) · International Journal of Biological Sciences · doi:10.7150/ijbs.7.645 · Cited by 103 · see citing works
Apoptosis in HepG2 cells exposed to high glucose
Chandrasekaran, K., Swaminathan, K., Chatterjee, S., & Dey, A. (2009) · Toxicology in Vitro · doi:10.1016/j.tiv.2009.10.020 · Cited by 100 · see citing works
García‐Monzón, C., Iacono, O. L., Mayoral, R., González‐Rodríguez, Á., Miquilena-Colina, M. E., Lozano-Rodríguez, T., García-Pozo, L., Vargas‐Castrillón, J., Casado, M., Boscá, L., et al. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.06.021 · Cited by 92 · see citing works
Ophiobolin A. A natural product inhibitor of calmodulin.
Leung, P. C. K., Taylor, W. A., Wang, J. H.-C., & Tipton, C. L. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)43208-x · Cited by 92 · see citing works
Self-citationShao, J., Qiao, L., Janssen, R. C., Pagliassotti, M. J., & Friedman, J. E. (2005) · Diabetes · doi:10.2337/diabetes.54.4.976 · Cited by 90 · see citing works
Zhu, B., Zhou, Y., Xu, F., Shuai, J., Li, X., & Fang, W. (2012) · Journal of Virology · doi:10.1128/jvi.01434-12 · Cited by 83 · see citing works
Hong, F., Nguyen, V.-A., Shen, X., Kunos, G., & Gao, B. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.4044 · Cited by 82 · see citing works
So, W. Y., Cheng, Q., Xu, A., Lam, K. S. L., & Leung, P. S. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.80 · Cited by 78 · see citing works
Self-citationCovington, M. D., & Schnellmann, R. G. (2011) · Kidney International · doi:10.1038/ki.2011.356 · Cited by 53 · see citing works
Renström, F., Burén, J., Svensson, M. K. E., & Eriksson, J. W. (2007) · Metabolism · doi:10.1016/j.metabol.2006.09.012 · Cited by 46 · see citing works
Kayampilly, P. P., & Menon, K. (2012) · Endocrinology · doi:10.1210/en.2011-1967 · Cited by 42 · see citing works
Tsintzas, K., Norton, L., Chokkalingam, K., Nizamani, N., Cooper, S., Stephens, F. B., Billeter-Clark, R., & Bennett, A. J. (2013) · Clinical Science · doi:10.1042/cs20120481 · Cited by 24 · see citing works
Impacts of Autophagy-Inducing Ingredient of Areca Nut on Tumor Cells
Yen, C., Chiang, W., Liu, S.-Y., Lin, C.-C., Liao, K.-A., Lin, C.-Y., Hsieh, W.-F., Cheng, Y.-C., Hsu, K., Lin, P.-Y., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0128011 · Cited by 15 · see citing works
High glucose reduces hepatic glycogenesis by suppression of microRNA-152
Zhao, X., Lu, Y., WANG, F., DOU, L., WANG, L., Guo, J., & Li, J. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.2426 · Cited by 11 · see citing works
Liu, W. N., & Leung, K. N. (2015) · Cancer Cell International · doi:10.1186/s12935-015-0246-5 · Cited by 10 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Irisin: A Hope in Understanding and Managing Obesity and Metabolic Syndrome
Arhire, L. I., Mihalache, L., & Covașă, M. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00524 · Cited by 306 · see citing works
“In fact, irisin levels are negatively associated with waist-to-hip ratio and with waist circumference (106) and a positive relationship between circulating irisin and body mass index has been reported (73, 104, 105, 118).”
BackgroundGao, Y., Zhang, W., Zeng, L.-Q., Bai, H., Li, J., Zhou, J., Zhou, G., Fang, C., Wang, F., & Qin, X.-J. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101635 · Cited by 293 · see citing works
“It was reported that exercise could induce irisin expression in the muscle and secretion into circulation to exert its effects on ameliorating hepatic glucose/lipid metabolism [65,66].”
BackgroundPolyzos, S. A., Anastasilakis, A. D., Efstathiadou, Z. A., Makras, P., Perakakis, N., Kountouras, J., & Mantzoros, C. S. (2018) · Endocrine · doi:10.1007/s12020-017-1476-1 · Cited by 262 · see citing works
Askari, H., Rajani, S. F., Poorebrahim, M., Haghi‐Aminjan, H., Raeis-Abdollahi, E., & Abdollahi, M. R. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.01.012 · Cited by 188 · see citing works
Qiongyue, Z., Xin, Y., Meng, P., Mi, S., Yanlin, W., Li, X., & Xuemin, S. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.857067 · Cited by 186 · see citing works
“Therefore, irisin may become an attractive pharmacological target for metabolic diseases (So and Leung, 2016; Askari et al., 2018; Yano et al., 2020; Özkur et al., 2020).”
BackgroundLi, Q., Tan, Y., Chen, S., Xiao, X., Zhang, M., Wu, Q., & Dong, M. (2020) · Journal of Receptors and Signal Transduction · doi:10.1080/10799893.2020.1808675 · Cited by 136 · see citing works
Pignataro, P., Dicarlo, M., Zerlotin, R., Zecca, C., Dell’Abate, M. T., Buccoliero, C., Logroscino, G., Colucci, S. C., & Grano, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041605 · Cited by 131 · see citing works
“skeletal muscles [11,19], increases hepatic glucose and lipid metabolism [20,21], displaying beneficial effects on metabolic disorders, such as diabetes [11,22].”
BackgroundFNDC5/Irisin inhibits pathological cardiac hypertrophy
Yu, Q., Kou, W., Xu, X., Zhou, S., Luan, P., Xu, X., Li, H., Zhuang, J., Wang, J., Zhao, Y., et al. (2019) · Clinical Science · doi:10.1042/cs20190016 · Cited by 115 · see citing works
Irisin inhibits pancreatic cancer cell growth via the AMPK-mTOR pathway
Liu, J., Song, N., Yi, H., & Chen, Y. (2018) · Scientific Reports · doi:10.1038/s41598-018-33229-w · Cited by 113 · see citing works
An update on the role of irisin in the regulation of endocrine and metabolic functions
Mahgoub, M., D’Souza, C. M., Darmaki, R. S. A., Baniyas, M. M. Y. H., & Adeghate, E. A. (2018) · Peptides · doi:10.1016/j.peptides.2018.03.018 · Cited by 109 · see citing works
“Reduces hepatic insulin resistance [15,16]”
Irisin promotes proliferation but inhibits differentiation in osteoclast precursor cells
Ma, Y., Qiao, X., Zeng, R., Cheng, R., Zhang, J., Luo, Y., Nie, Y., Hu, Y., Yang, Z., Zhang, J., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201700983rr · Cited by 90 · see citing works
Shi, G., Tang, N., Qiu, J., Zhang, D., Huang, F., Cheng, Y., Ding, K., Li, W., Zhang, P., & Tan, X. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.08.148 · Cited by 86 · see citing works
The Emerging Role of Irisin in Cardiovascular Diseases
Fu, J., Li, F., Tang, Y., Cai, L., Zeng, C., Yang, Y., & Yang, J. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.121.022453 · Cited by 72 · see citing works
Zhang, D., Xie, T., & Leung, P. S. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000495395 · Cited by 65 · see citing works
Self-citationIrisin: A Multifaceted Hormone Bridging Exercise and Disease Pathophysiology
Paoletti, I., & Coccurello, R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413480 · Cited by 70 · see citing works
“…irisin was shown to be able to improve hepatic IR induced by high glucose–high insulin conditions in human liver-derived HepG2 cells, by stimulating liver kinase B1 (LKB1) phosphorylation and, downstream, by triggering AMPK phosphorylation and suppressing acetyl-CoA-carboxylase (ACC) activity [46].”
Irisin acts as a regulator of macrophages host defense
Mazur-Biały, A. I. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.03.011 · Cited by 64 · see citing works
Marine Peptides as Potential Agents for the Management of Type 2 Diabetes Mellitus—A Prospect
Xia, E.-Q., Zhu, S., He, M.-J., Luo, F., Fu, C.-Z., & Zou, T. (2017) · Marine Drugs · doi:10.3390/md15040088 · Cited by 64 · see citing works
Adipokines, Myokines, and Cardiokines: The Role of Nutritional Interventions
Senesi, P., Luzi, L., & Terruzzi, I. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218372 · Cited by 61 · see citing works
“Indeed, irisin promotes glucose uptake by skeletal muscles and lipid metabolism [135,136].”
BackgroundMyokines: Metabolic regulation in obesity and type 2 diabetes
Chen, Z.-T., Weng, Z.-X., Lin, J. D., & Meng, Z.-X. (2024) · Life Metabolism · doi:10.1093/lifemeta/loae006 · Cited by 58 · see citing works
“Ex vivo studies have found that irisin ameliorates dysregulated glucose and lipid metabolism, and improves hepatic insulin resistance and cell survival under high glucose-high insulin conditions [104].”
Zhao, Y., Wang, J., Yano, N., Zhang, L. X., Wang, H., Zhang, S.-Y., Qin, G., Dubielecka, P., Zhuang, S., Liu, P., et al. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27037 · Cited by 57 · see citing works
“…it is likely that irisin can modify the cytokine profile and metabolism of cultured cells to modulate CPC‐derived cardiac repair (D. J. Li, Li, Yuan, Qu, & Wang, 2017; Lu et al., 2015; Park et al., 2015; So & Leung, 2016; Y. Zhang, Li, et al., 2014), which is of interest for future studies.”
BackgroundMarrano, N., Biondi, G., Borrelli, A., Cignarelli, A., Perrini, S., Laviola, L., Giorgino, F., & Natalicchio, A. (2021) · Biomolecules · doi:10.3390/biom11020286 · Cited by 56 · see citing works
Song, R., Zhao, X., Cao, R. Y., Liang, Y., Zhang, D., & Wang, R. (2020) · Gene · doi:10.1016/j.gene.2020.145209 · Cited by 52 · see citing works
(2020) · Advances in clinical chemistry · doi:10.1016/bs.acc.2019.07.012 · Cited by 46 · see citing works
Lower levels of irisin in patients with type 2 diabetes mellitus: A meta-analysis
Song, R., Zhao, X., Zhang, D., Wang, R., & Feng, Y. (2021) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2021.108788 · Cited by 45 · see citing works
Hepatic FNDC5 is a potential local protective factor against Non-Alcoholic Fatty Liver
Canivet, C. M., Bonnafous, S., Rousseau, D., Leclère, P. S., Lacas‐Gervais, S., Patouraux, S., Sans, A., Luci, C., Bailly‐Maitre, B., Iannelli, A., et al. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165705 · Cited by 44 · see citing works
Irisin, Exercise, and COVID-19
Alves, H. R., Lomba, G. S. B., Gonçalves-de-Albuquerque, C. F., & Burth, P. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.879066 · Cited by 39 · see citing works
Exercise-Induced Autophagy in Fatty Liver Disease
Chun, S. K., Lee, S., Yang, M., Leeuwenburgh, C., & Js, K. (2017) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000116 · Cited by 37 · see citing works
Babaei, P., Shirkouhi, S. G., Hoseini, R., & Tehrani, B. S. (2017) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-017-0288-z · Cited by 31 · see citing works
“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].”
BackgroundRole of Irisin in Endocrine and Metabolic Disorders—Possible New Therapeutic Agent?
Leuștean, L., Preda, C., Teodoriu, L. C., Mihalache, L., Arhire, L. I., & Ungureanu, M.-C. (2021) · Applied Sciences · doi:10.3390/app11125579 · Cited by 33 · see citing works
“The reduction in hepatic insulin resistance, weight and blood glucose levels, inhibition of gluconeogenesis, and stimulation of glycogenesis are the main metabolic effects attributable to irisin [1,23,24].”
BackgroundIrisin 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 · see citing works
Guo, 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 · see citing works
Fatima, S. S., Khalid, E., Ladak, A. A., & Ali, S. A. (2018) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.1080/14767058.2018.1454422 · Cited by 25 · see citing works
The Potential of Irisin as a Therapeutic for Diabetes
Leung, P. S. (2017) · Future Medicinal Chemistry · doi:10.4155/fmc-2017-0035 · Cited by 25 · see citing works
Self-citationThe interplay between the muscle and liver in the regulation of glucolipid metabolism
Cheng, C., Xie, L., Zhang, M., Shama, S., Cheng, K. K. Y., & Jia, W. (2023) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjad073 · Cited by 23 · see citing works
Balakumar, P., Venkatesan, K., Khan, N. A., Raghavendra, N. M., Venugopal, V., Bharathi, D. R., & Fuloria, N. K. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103627 · Cited by 22 · see citing works
Shaw, A., Tóth, B. B., Király, R., Arianti, R., Csomós, I., Póliska, S., Vámos, A., Korponay-Szabo, I. R., Bacsó, Z., Győry, F., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.737872 · Cited by 19 · see citing works
“However, other studies proposed positive effects of irisin on cAMP342 PKA-HSL (57), AMPK (58), (59), or p38 MAPK (18) pathways.”
BackgroundBellettini‐Santos, T., Batista-Silva, H., Pereira, C. M., Castro, F. C. D. A. Q., Barcelos, R. M., Chiepe, K. C. M. B., Rossoni, J. V., Ambrósio, R. P., da Silva, B. S., Chiarelli-Neto, O., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512440 · Cited by 15 · see citing works
“Irisin is a cleavage product of FNDC5 and acts as a myokine, as it has pleiotropic effects on peripheral tissues and the brain [8,9].”
BackgroundEffects of epoxy stearic acid on lipid metabolism in HepG2 cells
Liu, Y., Li, J., & Liu, Y. (2020) · Journal of Food Science · doi:10.1111/1750-3841.15405 · Cited by 15 · see citing works
Gaowa, A., Leangpanich, S., Park, E. J., Kawamoto, E., & Shimaoka, M. (2024) · Scientific Reports · doi:10.1038/s41598-024-76658-6 · Cited by 14 · see citing works
Liu, R., Zhang, Q., Peng, N., Xu, S., Zhang, M., Hu, Y., Chen, Z., Tang, K., He, X., Li, Y., et al. (2021) · BMC Cardiovascular Disorders · doi:10.1186/s12872-021-02380-0 · Cited by 13 · see citing works
“with an insulin-resistance state, irisin ameliorates glucose output and fat accumulation [41].”
BackgroundLi, A., Liu, J., Ding, F., Wu, X., Pan, C., Wang, Q., Gao, M., Duan, S., Han, X.-F., Xia, K., et al. (2021) · Food Science & Nutrition · doi:10.1002/fsn3.2246 · Cited by 13 · see citing works
The potential role of FNDC5/irisin in various liver diseases: awakening the sleeping beauties
Wang, X., Mao, L., Li, C., Hui, Y., Yu, Z., Sun, M., Li, Y., Guo, G., Yang, W., Cui, B., et al. (2022) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2022.19 · Cited by 12 · see citing works
Potential role of irisin in digestive system diseases
Zhang, Y., Zhao, L., Gao, H., Zhai, J., & Song, Y. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115347 · Cited by 10 · see citing works
Su, Y., Choi, H.-S., Choi, J.-H., Kim, H.-S., Lee, G.-Y., Cho, H.-W., Choi, H., Jang, Y., & Seo, J. (2023) · Nutrients · doi:10.3390/nu15020427 · Cited by 10 · see citing works
“Real-time PCR was employed to determine mRNA expression of adipogenesis genes in the liver, including (A) SREBP-1, (B) FAS, (C) PPARα, and (D) CPT-1.”
BackgroundInfluentialLi, X., Duan, H., Liu, Q., Umar, M., Luo, W., Yang, X., Zhu, J., & Li, M. (2018) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2018.11.092 · Cited by 10 · see citing works
Physical Exercise and Liver Autophagy: Potential Roles of IL-6 and Irisin
Pinto, A. P., Ropelle, E. R., Quadrilatero, J., & da Silva, A. S. R. (2021) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000278 · Cited by 10 · see citing works
“Irisin can activate AMPK in the liver, which will initiate autophagy via ULK1 phosphorylation (66,67).”
BackgroundIrisin Regulates Hepatic Glucose Metabolism via AMPK and PI3K/Akt Activation
Zhi, S.-Y., Yang, L., Yang, G.-K., Qin, C.-B., Yan, X., Niu, M.-M., Zhang, W., Liu, M., Zhao, M., & Nie, G. (2022) · Aquaculture Nutrition · doi:10.1155/2022/1946960 · Cited by 8 · see citing works
“At the same time, irisin can phosphorylate AMPK through LKB1, regulate acetyl-CoA carboxylase, and improve the body’s glucose tolerance, glucose uptake, and hepatic glucose and fat metabolism [16, 17].”
BackgroundEvaluation of pregnancy toxemia in goats: Metabolic profile, hormonal findings, and redox balance
Uzti̇mür, M., & Ünal, C. N. (2024) · Small Ruminant Research · doi:10.1016/j.smallrumres.2024.107385 · Cited by 8 · see citing works
Role of irisin in metabolic and cardiovascular disorders and its therapeutic potential
Khalil, R. G., Atia, T. A., Yousef, A. I., Sakr, H. I., & Ahmed, O. M. (2025) · Beni-Suef University Journal of Basic and Applied Sciences · doi:10.1186/s43088-025-00643-9 · Cited by 8 · see citing works
“…, l e a d i n g t o d e c r e a s e d h e p a t i c s t e a t o s i s a n d i m p r o v e d l i v e r f u n c t i o n i n T 2 D m o d e l s [ 133 , 154 ] I n fl a mm a t o r y r e s p o n s e D e c r e a s e s s y s t e m i c i n fl a mm a t i o n b y r e d u c - i n g p r o - i n fl a mm a t o r…”
Sadeghabadi, Z. A., Abbasalipourkabir, R., Mohseni, R., & Ziamajidi, N. (2019) · Archives of Physiology and Biochemistry · doi:10.1080/13813455.2019.1702060 · Cited by 8 · see citing works
“SIRT1 activates PGC-1a through deacetylation (Sadeghabadi et al. 2019).”
InfluentialShokrollahi, B., Jang, S.-S., Lee, H. J., Ahmad, H. I., Sesay, A. R., Shad, A. G. K., Morammazi, S., & Abdelnour, S. A. (2024) · Frontiers in Veterinary Science · doi:10.3389/fvets.2024.1435788 · Cited by 7 · see citing works
Roles of FGF21 and irisin in obesity-related diabetes and pancreatic diseases
Xie, T., & Leung, P. S. (2020) · Journal of Pancreatology · doi:10.1097/jp9.0000000000000039 · Cited by 7 · see citing works
Self-citationSun, L., Lu, J., Yao, D., Li, X., Cao, Y., Gao, J., Liu, J., Zheng, T., Wang, H. H., & Zhan, X. (2023) · Preventive Medicine · doi:10.1016/j.ypmed.2023.107576 · Cited by 7 · see citing works
Magdy, Y., Kamar, S. A., Fansa, H., Khedr, S. A., & Sedky, A. A. (2025) · The Egyptian Journal of Neurology Psychiatry and Neurosurgery · doi:10.1186/s41983-025-00960-x · Cited by 6 · see citing works
“Irisin crosses the blood–brain barrier [16] and regulates metabolism and communication between muscle and brain [17, 18].”
Yao, Z. J., Ding, X., Gao, X., Yang, N., Jia, Y., Liu, J., & Wang, G. (2021) · International Journal of Endocrinology · doi:10.1155/2021/3116068 · Cited by 6 · see citing works
A Comprehensive Review of Novel Biomarkers in the Diagnosis of Intrahepatic Cholestasis of Pregnancy
Liu, W. L., Chen, L., Wang, W., Yue, Z., Li, J., Tan, M., Gu, Y., Zhu, R., & Zhang, Y. (2023) · Biomarkers in Medicine · doi:10.2217/bmm-2023-0190 · Cited by 5 · see citing works
Irisin-mediated hepatic autophagy remodels nutritional metabolism to prevent cognitive dysfunction
Zhang, X., Yang, Y., Song, H., Hu, X., Wang, X., & Yu, Y. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102936 · Cited by 4 · see citing works
Wang, D., Zhu, F., Shao, M. M., Zang, H., & Xia, X. (2025) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-025-04681-z · Cited by 3 · see citing works
“Beyond its metabolic effects, Irisin exhibits diverse biological functions, including anti-inflammatory, anti-aging, and antioxidant properties, which are particularly relevant in metabolic disorders (So and Leung 2016; Özkur et al. 2020; Korta et al. 2019).”
Tang, N., Chen, Y., Wu, W., Pan, W., Wang, D., Zhang, J., Tan, K., Jin, J., & Cai, L. (2021) · Journal of Diabetes Investigation · doi:10.1111/jdi.13517 · Cited by 3 · see citing works
Yılmaz, F. Ç., Türkoğlu, S., & Erman, F. (2025) · European Journal of Pediatrics · doi:10.1007/s00431-025-06154-0 · Cited by 2 · see citing works
“It also helps lose weight by reducing glucose tolerance and fat mass [6, 7].”
Metabolic and immune links between sarcopenia and liver disease
Kotlyarov, S. N. (2025) · World Journal of Hepatology · doi:10.4254/wjh.v17.i8.109444 · Cited by 2 · see citing works
Irisin-Treg crosstalk: unveiling a mechanism in neural cognitive regulation
Zhan, R., Yang, J., Wan, Q., Zhang, J., Liu, L., Jiang, J., Mo, L., & Bai, Y. (2025) · Annals of Medicine · doi:10.1080/07853890.2025.2594281 · Cited by 2 · see citing works
“Studies indicate Irisin improves insulin resistance in diabetic mice and regulates glucose [97] and lipid metabolism in human hepatocytes [98].”
Wang, Y., Zhang, H., Wang, X., Zhang, Y., Fan, L., Ma, Y., & Liu, X. (2025) · Food Bioscience · doi:10.1016/j.fbio.2025.106442 · Cited by 2 · see citing works
Mansour, S. W., Hasan, M. M., Salah, H., El-Deep, T., Hussein, S., & El-Malkey, N. F. (2021) · Beni-Suef University Journal of Basic and Applied Sciences · doi:10.1186/s43088-021-00148-1 · Cited by 2 · see citing works
“These effects occur via activation of the 5′ adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, and acetylCoA-carboxylase in hepatic cells, an effect that plays a significant role in cellular energy homeostasis [26].”
BackgroundSerum Irisin In Individuals with Type 2 Diabetes Mellitus and Prediabetes in Duhok City
Ibrahim, I., & Salih, S. (2022) · Journal of Life and Bio Sciences Research · doi:10.38094/jlbsr30277 · Cited by 2 · see citing works
Guedes, J. M., G. Peluzio, M. D. C., Rathmacher, J. A., Leal, T. F., Carneiro Júnior, M. A., de Carvalho, D. M., de Oliveira, L. L., & Natali, A. J. (2021) · Biology of Sport · doi:10.5114/biolsport.2020.97671 · Cited by 1 · see citing works
Zarzecka, B., Dobrzyń, K., Kieżun, M., Kopij, G., Dawid, M., Rak, A., Dall’Aglio, C., Kamiński, T., & Smolińska, N. (2025) · Reproduction Fertility and Development · doi:10.1071/rd25057 · Cited by 1 · see citing works
Anadolu Merinoslarında İrisin Hormon Yanıtı Üzerine Bazı Fizyolojik Parametrelerin Etkisi
Bayraktar, B., & Tekçe, E. (2021) · Etlik Veteriner Mikrobiyoloji Dergisi · doi:10.35864/evmd.954977 · Cited by 1 · see citing works
Research Progress of Irisin in Obesity and Related Metabolic Diseases
Zhang, Y.-N. (2023) · Advances in Clinical Medicine · doi:10.12677/acm.2023.13122830 · Cited by 1 · see citing works
From Liver to Muscle: Crosstalk Mechanisms and Interventions in Sarcopenia
Wang, Q., Meng, Y., Wang, X., Lan, X., Fan, G., & Xiang, Y. (2025) · Health and Metabolism · doi:10.53941/hm.2025.100022 · Cited by 1 · see citing works
Irisina: ruolo nell’omeostasi del glucosio
Natalicchio, A., Marrano, N., & Giorgino, F. (2018) · L Endocrinologo · doi:10.1007/s40619-018-00498-6 · Cited by 1 · see citing works
Elkattawy, H. A., & Ashour, W. M. R. (2019) · Al-Azhar Medical Journal · doi:10.21608/amj.2019.56675 · Cited by 1 · see citing works
Yıldırım, I. (2018) · International Cell Death Research Congress · doi:10.3390/proceedings2251561
“Another study identified that Irisin induced cell death of HepG2 cells by phosphorylation of AMPK and acetyl-CoAcarboxylase (ACC) via liver kinase B1 (LKB1) [4].”
BackgroundGülmez, C., & Atakişi, O. (2020) · Veterinarski arhiv · doi:10.24099/vet.arhiv.0928
Rodríguez, A. M., Bonet, M. L., & Ribot, J. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813814-4.00026-2
Almousawy, M. H., & Jabir, F. A. (2022) · Pakistan Journal of Medical and Health Sciences · doi:10.53350/pjmhs22164953
Irisina: un singolo ormone, molti cross-talk
Natalicchio, A., Marrano, N., & Giorgino, F. (2023) · il Diabete · doi:10.30682/ildia2302b
The Potential Protective Mechanisms of Exercise-Responsive Molecules in Chronic Kidney Disease
Chang, J. S. (2024) · Exercise Science · doi:10.15857/ksep.2024.00472
Research advances in the association between Irisin and obstructive sleep apnea
Luyao, S., Chao, W., Pan, L., & Jinxiang, G. (2025) · Sleep And Breathing · doi:10.1007/s11325-025-03550-6
“Additionally, irisin activates AMP-activated protein kinase (AMPK), ameliorating hepatic glucose/lipid dysmetabolism and cell death under insulin-resistant conditions [22].”
Jeon, Y., Lee, H., Hong, S., Kim, H., Kim, Y., & Lee, J. (2025) · International Journal of Food Science & Technology · doi:10.1093/ijfood/vvag113
Sahare, H., Tatode, A., Qutub, M., Umekar, M. J., Taksande, B. G., Premchandani, T., & Nalkande, S. (2026) · Obesity Medicine · doi:10.1016/j.obmed.2026.100730
Gao, R., Zhang, Y., & Quan, L. (2026) · Comprehensive physiology · doi:10.1002/cph4.70248
Cañate, D. C., Araos, P. A., & Bolívar, S. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48101036
“In contrast, in human HepG2 cells, irisin-induced AMPK activation was associated predominantly with liver kinase B1 (LKB1) rather than CaMKK β [60].”
Potential role of irisin-mediated oxidative stress defense in systemic diseases
Xiao, X., 吴丽颖, Zhu, X., & Zhou, J. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1996659
- Authors
- So, W. Y., & Leung, P. S.
- Affiliations
- Chinese University of Hong Kong (HK)
- Corresponding author
- So, Wing Yan
- Leung, Po Sing
- Venue
- The International Journal of Biochemistry & Cell Biology
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 78
- Pages
- 237-247
- ISSN
- 1357-2725 (ISSN-L)
- OpenAlex
- W2479660582
- Cited by
- 83
- References
- 58
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 6 · 2023: 10 · 2022: 6 · 2021: 13 · 2020: 9 · 2019: 7 · 2018: 9 · 2017: 7
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The International Journal of Biochemistry & Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- General Research Fund of The Research Grants Council of the Hong Kong Special Administrative Region, China (CUHK14110314)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- irisin, AMPK signaling, hepatic insulin resistance, hepatic glucose metabolism, hepatic lipid metabolism, LKB1, acetyl-CoA carboxylase, ERK1/2 phosphorylation, cell survival, HepG2 cells, type 2 diabetes, myokines, triglyceride accumulation, glycogen content
- MeSH terms
- Acetyl-CoA Carboxylase, Cell Survival, Enzyme Activation, Fibronectins, Glucose, Humans, Insulin Resistance, Liver, Phosphorylation, Triglycerides, Signal Transduction, Mitogen-Activated Protein Kinase 1, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 3, AMP-Activated Protein Kinases, Hep G2 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
