Treatment of type 2 diabetes with the designer cytokine IC7Fc
Open accessAbstract
The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.
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In these same contexts, others have shown that IL6 induces insulin sensitivity, while IL6 has been shown to be insulin sensitizing in exercise.
“On the other hand, in these same contexts, others have shown that IL6 induces insulin sensitivity (Carey et al., 2006; Findeisen et al., 2019; Matthews et al., 2010; Mauer et al., 2014; Steensberg et al., 2003; Timper et al., 2017), while IL6 has been shown to be insulin sensitizing in exercise (Benrick et al., 2012).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Findeisen et al., 2019
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Cites
Analyzing real-time PCR data by the comparative CT method
Schmittgen, T. D., & Livak, K. J. (2008) · Nature Protocols · doi:10.1038/nprot.2008.73 · Cited by 26,190 · see citing works
Wild, S., Roglic, G., Green, A., Sicree, R., & King, H. (2004) · Diabetes Care · doi:10.2337/diacare.27.5.1047 · Cited by 15,297 · see citing works
Danaei, G., Finucane, M. M., Lu, Y., Singh, G. M., Cowan, M. J., Paciorek, C. J., Lin, J. K., Farzadfar, F., Khang, Y.-H., Stevens, G. A., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60679-x · Cited by 3,568 · see citing works
Effect of pegylation on pharmaceuticals
Harris, J. M., & Chess, R. B. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1033 · Cited by 3,431 · see citing works
Sarcopenia: Aging-Related Loss of Muscle Mass and Function
Larsson, L., Degens, H., Li, M., Salviati, L., Lee, Y. I., Thompson, W., Kirkland, J. L., & Sandri, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00061.2017 · Cited by 1,797 · see citing works
Ellingsgaard, H., Hauselmann, I., Schuler, B., Habib, A. M., Baggio, L. L., Meier, D. T., Eppler, E., Bouzakri, K., Wueest, S., Muller, Y. D., et al. (2011) · Nature Medicine · doi:10.1038/nm.2513 · Cited by 922 · see citing works
Carey, A. L., Steinberg, G. R., Macaulay, S. L., Thomas, W. G., Holmes, A. G., Ramm, G., Prelovsek, O., Hohnen-Behrens, C., Watt, M. J., James, D. E., et al. (2006) · Diabetes · doi:10.2337/db05-1404 · Cited by 898 · see citing works
Srikanthan, P., & Karlamangla, A. S. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0435 · Cited by 785 · see citing works
A gp130–Src–YAP module links inflammation to epithelial regeneration
Taniguchi, K., Wu, L.-W., Grivennikov, S. I., de Jong, P. R., Lian, I., Yu, F.-X., Wang, K., Ho, S. B., Boland, B. S., Chang, J. T., et al. (2015) · Nature · doi:10.1038/nature14228 · Cited by 633 · see citing works
The Hippo pathway effector YAP controls mouse hepatic stellate cell activation
Mannaerts, I., Leite, S. B., Verhulst, S., Claerhout, S., Eysackers, N., Thoen, L. F. R., Hoorens, A., Reynaert, H., Halder, G., & van Grunsven, L. A. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.04.011 · Cited by 410 · see citing works
ALS CNTF Treatment Study Group (1996) · Neurology · doi:10.1212/wnl.46.5.1244 · Cited by 405 · see citing works
Effect of Exercise Intensity on Skeletal Muscle AMPK Signaling in Humans
Chen, Z.-P., Stephens, T. J., Murthy, S., Canny, B. J., Hargreaves, M., Witters, L. A., Kemp, B. E., & McConell, G. K. (2003) · Diabetes · doi:10.2337/diabetes.52.9.2205 · Cited by 369 · see citing works
Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance
Matthews, V. B., Allen, T. L., Risis, S., Chan, M. H. S., Henstridge, D. C., Watson, N., Zaffino, L. A., Babb, J. R., Boon, J., Meikle, P. J., et al. (2010) · Diabetologia · doi:10.1007/s00125-010-1865-y · Cited by 334 · see citing works
Hansotia, T., Baggio, L. L., Delmeire, D., Hinke, S. A., Yamada, Y., Tsukiyama, K., Seino, Y., Holst, J. J., Schuit, F., & Drucker, D. J. (2004) · Diabetes · doi:10.2337/diabetes.53.5.1326 · Cited by 309 · see citing works
Self-citationGlaesner, W., Vick, A., Millican, R. L., Ellis, B., Tschang, S., Tian, Y., Bokvist, K. B., Brenner, M. B., Köester, A., Pørksen, N. K., et al. (2010) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.1080 · Cited by 305 · see citing works
Hezareh, M., Hessell, A. J., Jensen, R. C., van de Winkel, J. G. J., & Parren, P. W. H. I. (2001) · Journal of Virology · doi:10.1128/jvi.75.24.12161-12168.2001 · Cited by 294 · see citing works
Nauck, M., Weinstock, R. S., Umpierrez, G. E., Guerci, B., Skrivanek, Z., & Milicevic, Z. (2014) · Diabetes Care · doi:10.2337/dc13-2761 · Cited by 284 · see citing works
The Ever-Expanding Myokinome: Discovery Challenges and Therapeutic Implications
Whitham, M., & Febbraio, M. A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.153 · Cited by 279 · see citing works
CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK
Watt, M. J., Dzamko, N. L., Thomas, W. G., Rose‐John, S., Ernst, M., Carling, D., Kemp, B. E., Febbraio, M. A., & Steinberg, G. R. (2006) · Nature Medicine · doi:10.1038/nm1383 · Cited by 275 · see citing works
Kraakman, M. J., Kammoun, H. L., Allen, T. L., Deswaerte, V., Henstridge, D. C., Estevez, E., Matthews, V. B., Neill, B., White, D. A., Murphy, A. J., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.02.006 · Cited by 257 · see citing works
Self-citationScheidt‐Nave, C., Bismar, H., Leidig‐Bruckner, G., Woitge, H. W., Seibel, M. J., Ziegler, R., & Pfeilschifter, J. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.5.7445 · Cited by 255 · see citing works
Transgenic blockade of interleukin 6 transsignaling abrogates inflammation
Rabe, B., Chalaris, A., May, U., Waetzig, G. H., Seegert, D., Williams, A. S., Jones, S. A., Rose‐John, S., & Scheller, J. (2007) · Blood · doi:10.1182/blood-2007-07-102137 · Cited by 244 · see citing works
Ettinger, M. P., Littlejohn, T. W., Schwartz, S. L., Weiss, S. R., McIlwain, H. H., Heymsfield, S. B., Bray, G. A., Roberts, W. G., Heyman, E. R., Stambler, N., et al. (2003) · PubMed · doi:10.1001/jama.289.14.1826 · Cited by 206 · see citing works
The Hippo pathway effector YAP is a critical regulator of skeletal muscle fibre size
Watt, K. I., Turner, B. J., Hagg, A., Zhang, X., Davey, J. R., Qian, H., Beyer, C., Winbanks, C. E., Harvey, K. F., & Gregorevic, P. (2015) · Nature Communications · doi:10.1038/ncomms7048 · Cited by 164 · see citing works
Self-citationGlucose-dependent insulinotropic peptide-overexpressing transgenic mice have increased bone mass
Xie, D., Zhong, Q., Ding, K.-H., Cheng, H., Williams, S., Correa, D., Bollag, W. B., Bollag, R. J., Insogna, K., Troiano, N., et al. (2007) · Bone · doi:10.1016/j.bone.2007.01.007 · Cited by 144 · see citing works
Role of interleukins in obesity: implications for metabolic disease
Febbraio, M. A. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.02.004 · Cited by 130 · see citing works
gp130 receptor ligands as potential therapeutic targets for obesity
Febbraio, M. A. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30453 · Cited by 124 · see citing works
Receptor Recognition Sites of Cytokines Are Organized as Exchangeable Modules
Kallen, K., Grötzinger, J., Lelièvre, E., Vollmer, P., Aasland, D., Renné, C., Müllberg, J., Büschenfelde, K. M. Z., Gascan, H., & Rose‐John, S. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.17.11859 · Cited by 102 · see citing works
Steinberg, G. R., Watt, M. J., Fam, B. C., Proietto, J., Andrikopoulos, S., Allen, A. M., Febbraio, M. A., & Kemp, B. E. (2006) · Endocrinology · doi:10.1210/en.2005-1587 · Cited by 101 · see citing works
Jazayeri, J. A., & Carroll, G. J. (2008) · BioDrugs · doi:10.2165/00063030-200822010-00002 · Cited by 100 · see citing works
Thiazolidinedione‐induced skeletal fragility – mechanisms and implications
Grey, A. B. (2008) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2008.00931.x · Cited by 88 · see citing works
Rakemann, T., Niehof, M., Kubicka, S., Fischer, M., Manns, M. P., Rose‐John, S., & Trautwein, C. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.3.1257 · Cited by 66 · see citing works
Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance
Brandon, A. E., Liao, B. M., Diakanastasis, B., Parker, B. L., Raddatz, K., McManus, S. A., O’Reilly, L., Kimber, E., van der Kraan, A. G. J., Hancock, D., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.013 · Cited by 63 · see citing works
Jordy, A. B., Kraakman, M. J., Gardner, T., Estévez, E., Kammoun, H. L., Weir, J. M., Kiens, B., Meikle, P. J., Febbraio, M. A., & Henstridge, D. C. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00547.2014 · Cited by 51 · see citing works
Kowalski, G. M., Kloehn, J., Burch, M. L., Selathurai, A., Hamley, S., Bayol, S. A., Lamon, S., Watt, M. J., Lee, R. S., McConville, M. J., et al. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2014.12.002 · Cited by 46 · see citing works
Pál, M., Wunderlich, C. M., Spohn, G., Brönneke, H. S., Schmidt‐Supprian, M., & Wunderlich, F. T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054247 · Cited by 42 · see citing works
Complex interplay among adiposity, insulin resistance and bone health
Ma, C., Tonks, K. T. T., Samocha‐Bonet, D., & Greenfield, J. R. (2018) · Clinical Obesity · doi:10.1111/cob.12240 · Cited by 36 · see citing works
Tibble, C., Cavaiola, T. S., & Henry, R. R. (2013) · Expert Review of Endocrinology & Metabolism · doi:10.1586/eem.13.20 · Cited by 25 · see citing works
Ciliary Neurotrophic Factor: a Role in Obesity?
Duff, E., & Baile, C. A. (2003) · Nutrition Reviews · doi:10.1301/nr.2003.dec.423-426 · Cited by 23 · see citing works
Askmyr, M., White, K. E., Jovic, T., King, H. A. D., Quach, J., Maluenda, A. C., Baker, E. K., Smeets, M. F. M. A., Walkley, C. R., & Purton, L. E. (2015) · Scientific Reports · doi:10.1038/srep15529 · Cited by 20 · see citing works
Henstridge, D. C., Estévez, E., Allen, T. L., Heywood, S. E., Gardner, T., Yang, C., Mellett, N. A., Kingwell, B. A., Meikle, P. J., & Febbraio, M. A. (2015) · Cell Stress and Chaperones · doi:10.1007/s12192-015-0571-6 · Cited by 10 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Inflammation in obesity, diabetes, and related disorders
Rohm, T. V., Meier, D. T., Olefsky, J. M., & Donath, M. Y. (2022) · Immunity · doi:10.1016/j.immuni.2021.12.013 · Cited by 2,066 · see citing works
Origin and function of stress-induced IL-6 in murine models
Qing, H., Desrouleaux, R., Israni-Winger, K., Mineur, Y. S., Fogelman, N., Zhang, C., Rashed, S., Palm, N. W., Sinha, R., Picciotto, M. R., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.054 · Cited by 303 · see citing works
“On the other hand, in these same contexts, others have shown that IL6 induces insulin sensitivity (Carey et al., 2006; Findeisen et al., 2019; Matthews et al., 2010; Mauer et al., 2014; Steensberg et al., 2003; Timper et al., 2017), while IL6 has been shown to be insulin sensitizing in exercise (Benrick et al.”
Egan, B., & Sharples, A. P. (2023) · Physiological Reviews · doi:10.1152/physrev.00054.2021 · Cited by 278 · see citing works
The ever-changing roles of serotonin
Jones, L. A., Sun, E. W. L., Martin, A. M., & Keating, D. J. (2020) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2020.105776 · Cited by 241 · see citing works
Emerging principles of cytokine pharmacology and therapeutics
Saxton, R. A., Glassman, C. R., & García, K. C. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00557-6 · Cited by 223 · see citing works
De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2
Linsky, T. W., Vergara, R., Codina, N., Nelson, J. W., Walker, M. J., Su, W., Barnes, C. O., Hsiang, T.-Y., Esser-Nobis, K., Yu, K., et al. (2020) · Science · doi:10.1126/science.abe0075 · Cited by 216 · see citing works
Adipokines: masterminds of metabolic inflammation
Tilg, H., Ianiro, G., Gasbarrini, A., & Adolph, T. E. (2024) · Nature reviews. Immunology · doi:10.1038/s41577-024-01103-8 · Cited by 219 · see citing works
“…removed from IL-6 and replaced with the leukaemia inhibitory factor (LIF) receptor-binding site from ciliary neurotrophic factor (CNTF) to generate a cytokine with both CNTF-like and IL-6R-dependent signalling — improved glucose tolerance, hyper-glycaemia and hepatic steatosis in obese mice 169 .”
“Sweet death”: Fructose as a metabolic toxin that targets the gut-liver axis
Febbraio, M. A., & Karin, M. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.09.004 · Cited by 177 · see citing works
“IC7Fc prevented high-fat-diet-induced insulin resistance and NAFLD, while preserving muscle mass through YAP activation (Findeisen et al., 2019).”
BackgroundMethodInfluentialIrisin ameliorates age‐associated sarcopenia and metabolic dysfunction
Guo, M., Yao, J., Li, J., Zhang, J., Wang, D., Zuo, H., Zhang, Y., Xu, B., Zhong, Y., Shen, F., et al. (2022) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13141 · Cited by 166 · see citing works
“Besides, other long-acting Fc-apelin fusion protein such as NRG1-Fc and IC7-Fc have been tested clinically for diabetes treatment.(32,33) Second, albumin is the most abundant plasma protein.”
BackgroundInterleukin-6 signalling in health and disease
Rose‐John, S. (2020) · F1000Research · doi:10.12688/f1000research.26058.1 · Cited by 164 · see citing works
Zheng, X., Wu, Y., Bi, J., Huang, Y., Cheng, Y., Li, Y., Wu, Y., Cao, G., & Tian, Z. (2022) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00786-6 · Cited by 155 · see citing works
“are actively promoting a phase-I clinical trial of IC7FC, which they present as a very promising therapy for type-2 diabetes mellitus in the future [115].”
BackgroundNew insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology
Giraldez, M. D., Carneros, D., Garbers, C., Rose-John, S., & Bustos, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00473-x · Cited by 156 · see citing works
Li, L., Cui, L., Lin, P., Liu, Z., Bao, S., Ma, X., Nan, H., Zhu, W., Cen, J., Mao, Y., et al. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.01.009 · Cited by 134 · see citing works
Strategies to therapeutically modulate cytokine action
Leonard, W. J., & Lin, J. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00746-x · Cited by 121 · see citing works
Metcalfe, R. D., Putoczki, T. L., & Griffin, M. D. W. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01424 · Cited by 112 · see citing works
AMPK and the Endocrine Control of Metabolism
Townsend, L. K., & Steinberg, G. R. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad012 · Cited by 107 · see citing works
Diet-induced gut dysbiosis and inflammation: Key drivers of obesity-driven NASH
Kang, G. G., Trevaskis, N. L., Murphy, A. J., & Febbraio, M. A. (2023) · iScience · doi:10.1016/j.isci.2022.105905 · Cited by 94 · see citing works
“Made from the combination of two different cytokines (IL-6 and ciliary neurotrophic factor [CNTF]), IC7Fc modifies food intake and body weight and improves insulin resistance, thereby improving metabolic homeostasis in mice.(235) ILC7Fc is an interesting candidate to test for therapeutic potential in NAFLD and NASH.”
BackgroundSelf-citationPostprandial glucose spikes, an important contributor to cardiovascular disease in diabetes?
Hanssen, N. M. J., Kraakman, M. J., Flynn, M. C., Nagareddy, P. R., Schalkwijk, C. G., & Murphy, A. J. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.570553 · Cited by 90 · see citing works
“When administered tomouse models of obesity and diabetes, IC7Fc was able to prevent weight gain and in turn improve glucose tolerance and hyperglycemia, along with protecting the liver from steatosis (84).”
BackgroundMethodInfluentialAkram, N., Faisal, Z., Irfan, R., Shah, Y. A., Batool, S. A., Zahid, T., Zulfiqar, A., Fatima, A., Jahan, Q., Tariq, H., et al. (2023) · Food Science & Nutrition · doi:10.1002/fsn3.3826 · Cited by 87 · see citing works
“It is common knowledge that enteroendocrine cells perform the function of sensory cells and are capable of re-acting to their immediate surroundings (Findeisen et al., 2019; Lund et al., 2018; Sun et al., 2019).”
BackgroundThe Role of the Skeletal Muscle Secretome in Mediating Endurance and Resistance Training Adaptations
Leuchtmann, A. B., Adak, V., Dilbaz, S., & Handschin, C. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.709807 · Cited by 84 · see citing works
Targeting Inflammatory Cytokines to Improve Type 2 Diabetes Control
Velikova, T. V., Kabakchieva, P., Assyov, Y. S., & Georgiev, T. (2021) · BioMed Research International · doi:10.1155/2021/7297419 · Cited by 84 · see citing works
“Besides, through activating the YAP1 (yes-associated protein 1) transcriptional regulator, skeletal muscle mass was preserved [66].”
BackgroundInfluentialExerkines and cardiometabolic benefits of exercise: from bench to clinic
Jin, L., Díaz-Cañestro, C., Wang, Y., Tse, M. A., & Xu, A. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00027-z · Cited by 68 · see citing works
“In preclinical studies, both CNTF and IC7Fc potently reduce obesity and related metabolic complications (Findeisen et al, 2019; Gloaguen et al, 1997; Sleeman et al, 2003).”
BackgroundObesity, diabetes, and inflammation: Pathophysiology and clinical implications
Donath, M. Y., & Drucker, D. J. (2025) · Immunity · doi:10.1016/j.immuni.2025.09.011 · Cited by 64 · see citing works
Physiological role of cytokines in the regulation of mammalian metabolism
Baat, A. D., Trinh, B., Ellingsgaard, H., & Donath, M. Y. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.06.002 · Cited by 58 · see citing works
IL-6 and diabetic kidney disease
Zhang, L., Xu, F., & Hou, L.-Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1465625 · Cited by 50 · see citing works
Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease
Watt, K., Henstridge, D., Ziemann, M., Sim, C., Montgomery, M., Samocha-Bonet, D., Parker, B., Dodd, G., Bond, S., Salmi, T. M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23240-7 · Cited by 38 · see citing works
Crosstalk between Metabolic Disorders and Immune Cells
Saitoh, S., van Wijk, K., & Nakajima, O. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221810017 · Cited by 44 · see citing works
Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC
Boslem, E., Reibe, S., Carlessi, R., Smeuninx, B., Tegegne, S., Egan, C. L., McLennan, E., Terry, L. V., Nobis, M., Mu, A., et al. (2023) · Science Advances · doi:10.1126/sciadv.adh0831 · Cited by 39 · see citing works
“…of the membrane-bound IL-6 receptor (IL-6R)/gp130 signaling pathway that supports maintenance of gut barrier integrity ( 14 , 26 ) and adenosine monophosphate (AMP) – activated protein kinase (AMPK) – mediated increases in FAO ( 27 , 28 ), resulting in prevention of hepatic steatosis ( 28 , 29 ).”
Current and Future Treatments in the Fight against Non-Alcoholic Fatty Liver Disease
Smeuninx, B., Boslem, E., & Febbraio, M. A. (2020) · Cancers · doi:10.3390/cancers12071714 · Cited by 39 · see citing works
“IC7Fc activates the IL-6 signalling cascade, but in a completely unique manner and leads to weight loss, decreased food intake, and an increased incretin response [74].”
Backgroundder Stede, T. V., Blancquaert, L., Stassen, F., Everaert, I., Thienen, R. V., Vervaet, C., Gliemann, L., Hellsten, Y., & Derave, W. (2021) · Science Advances · doi:10.1126/sciadv.abf2856 · Cited by 39 · see citing works
Bruce, C. R., Hamley, S., Ang, T., Howlett, K. F., Shaw, C. S., & Kowalski, G. M. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101281 · Cited by 37 · see citing works
Trends in Therapeutic Conjugates: Bench to Clinic
Rudra, A., Li, J., Shakur, R., Bhagchandani, S. H., & Langer, R. (2020) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.9b00828 · Cited by 35 · see citing works
Li, S., Zhou, X., Zeng, R., Lin, L., Zou, X., Yan, Y., Lu, Z., Xia, J., Zhang, L., Ni, S.-Z., et al. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.10.323 · Cited by 31 · see citing works
mAChR4 suppresses liver disease via GAP-induced antimicrobial immunity
Llorente, C., Tonetti, F. R., Bruellman, R., Brea, R., Pell, N., Hartmann, P., Maccioni, L., Han, H., Cabré, N., Liu, J., et al. (2025) · Nature · doi:10.1038/s41586-025-09395-z · Cited by 26 · see citing works
der Stede, T. V., de Loock, A. V., Turiel, G., Hansen, C. C., Tamariz‐Ellemann, A., Ullrich, M., Lievens, E., Spaas, J., Yigit, N., Anckaert, J., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2024.12.011 · Cited by 25 · see citing works
Recent advances in the role of interleukin-6 in health and disease
Peppler, W. T., Townsend, L. K., & Wright, D. C. (2020) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2020.04.010 · Cited by 21 · see citing works
Scapin, G., Çağdaş, E., Grav, L. M., Lewis, N. E., Goletz, S., & Hafkenscheid, L. (2024) · Biotechnology Advances · doi:10.1016/j.biotechadv.2024.108467 · Cited by 18 · see citing works
Ding, Y., Chi, H., Shao, J., Shi, T., Yu, H. T., Wang, X., & Wang, X. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.676 · Cited by 17 · see citing works
Wang, Y., Wu, J., Yao, J., Chen, J., Cheng, K. K. Y., Ho, M. Y.-M., Lee, C., Lam, K. S. L., Tse, M. A., Panagiotou, G., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.10.013 · Cited by 16 · see citing works
Yeung, M. H. Y., Leung, K. L., Choi, L. Y., Yoo, J. S., Yung, S., So, P.-K., & Wong, C.-M. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.777395 · Cited by 14 · see citing works
“As previously reported (Findeisen et al., 2019; Park et al., 2019; Svendsen et al., 2020; Hupa-Breier et al., 2021), treatment of dulaglutide lowered the body weight (Figure 1B) by reducing the fat mass (Figure 1C and Supplementary Figures S1A−F), improved glucose homeostasis (Figures 1D–G), and reduced the energy exp…”
Obesity and the cerebral cortex: Underlying neurobiology in mice and humans
Patel, Y., Woo, A., Shi, S. S. W., Ayoub, R., Shin, J., Botta, A. M., Ketela, T., Sung, H., Lerch, J. P., Nieman, B. J., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.04.033 · Cited by 14 · see citing works
“To best evaluate the effect of obesity, we employed a HFD model that is used commonly within the literature (Findeisen, 2019; Chao, 2022; Kim et al., 2019), and that parallels human obesogenic diets rich in fat (Speakman, 2019).”
Venema, W., Severi, I., Perugini, J., Mercurio, E. D., Mainardi, M., Maffei, M., Cinti, S., & Giordano, A. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00140 · Cited by 14 · see citing works
More and more pleiotropy within the IL ‐6 family of cytokines
Rose‐John, S., & Jones, S. A. (2024) · FEBS Journal · doi:10.1111/febs.17355 · Cited by 13 · see citing works
“Interestingly, this also applies to a chimeric engineered cytokine called IC7, which contains a binding site to IL-6R, gp130, and LIFR and which has shown promising results in the treatment of type 2 diabetes and muscle atrophy [6,7].”
Dong, J., Viswanathan, S., Adami, E., Schäfer, S., Kuthubudeen, F. F., Widjaja, A. A., & Cook, S. A. (2021) · eLife · doi:10.7554/elife.68843 · Cited by 14 · see citing works
“, 2012) or the recently described IC7Fc fusion molecule (Findeisen et al., 2019).”
BackgroundLiu, T., Wang, Q., Zhou, L., Zhang, P., Mi, L., Qiu, X., Chen, Z., Kuang, H., Li, S., & Lin, J. D. (2022) · Hepatology · doi:10.1002/hep.32719 · Cited by 13 · see citing works
“[34] Although most of IL ‐ 6 family cytokines have been shown to be beneficial to hepatic metabolism and liver fibrogenesis, oncostatin M (Osm) overexpression in mouse liver promotes the development of severe fibrosis, [35] illustrating complex action of the IL ‐ 6 family cytokines in hepatic…”
BackgroundIL-6 family cytokines as potential therapeutic strategies to treat metabolic diseases
Zhao, J., Turpin-Nolan, S. M., & Febbraio, M. A. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155549 · Cited by 12 · see citing works
Exploring the landscape of synthetic IL ‐6‐type cytokines
Scheller, J., Ettich, J., Wittich, C., Pudewell, S., Floss, D. M., & Rafii, P. (2023) · FEBS Journal · doi:10.1111/febs.16909 · Cited by 12 · see citing works
“Of note, IC7 as an Fc-fusion protein (IC7Fc) had an increased bioavailability and showed no safety issues in nonhuman primates [120].”
BackgroundInfluentialMolecular origin and biological effects of exercise mimetics
Zhu, Y., & Song, G. (2023) · Journal of Exercise Science & Fitness · doi:10.1016/j.jesf.2023.12.002 · Cited by 14 · see citing works
“10 This is the first potential drug developed and validated using the exercise mimetic development strategy.”
BackgroundMethodMicrowave Measurement of Bovine Serum Albumin Solutions Based on High-Q/High-Resolution Resonator
Cui, Y., Zhang, Z., Sui, S., & Zhu, W. (2022) · IEEE Transactions on Microwave Theory and Techniques · doi:10.1109/tmtt.2022.3182710 · Cited by 12 · see citing works
Rafii, P., Cruz, P. R., Ettich, J., Seibel, C., Padrini, G., Wittich, C., Lang, A., Petzsch, P., Köhrer, K., Moll, J. M., et al. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107251 · Cited by 11 · see citing works
“As previously described, IC7 induced the proliferation of Ba/F3-IL-6R:gp130:LIFR cells (21) but also of Ba/F3-IL-6R:gp130:OSMR cells (Fig.”
InfluentialRafii, P., Seibel, C., Weitz, H. T., Ettich, J., Minafra, A. R., Petzsch, P., Lang, A., Floss, D. M., Behnke, K., Köhrer, K., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-04768-4 · Cited by 10 · see citing works
Weitz, H. T., Ettich, J., Rafii, P., Wittich, C., Schultz, L., Frank, N. C., Heise, D., Krusche, M., Lokau, J., Garbers, C., et al. (2024) · FEBS Journal · doi:10.1111/febs.17309 · Cited by 10 · see citing works
Interleukins in adipose tissue: Keeping the balance
Antuna-Puente, B. P., Fellahi, S., McAvoy, C., Fève, B., & Bastard, J. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111531 · Cited by 11 · see citing works
Le, V. T. B., Tsimbalyuk, S., Lim, E. Q., Solis, A., Gawat, D., Boeck, P., Lim, E. Q., Renolo, R., Forwood, J. K., & Kuhn, M. L. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.645768 · Cited by 9 · see citing works
“, 2008), and as drugs for type 2 diabetes (Findeisen et al., 2019).”
BackgroundBerg, R. M. G. (2025) · The Journal of Physiology · doi:10.1113/jp289744 · Cited by 8 · see citing works
“…2022; Severinsen & Pedersen, 2020), but has also led to the development of promising pharmacological agents shown to improve glucose tolerance and prevent weight gain, hepatic steatosis and loss of muscle mass in experimental models of obesity and type 2 diabetes mellitus (Findeisen et al., 2019).”
Dysfunctional adipose tissue–lymphatic crosstalk in obesity
Nardo, W. D., Chan, A. Y., Porter, C. J. H., Cao, E., & Trevaskis, N. L. (2026) · Nature Reviews Endocrinology · doi:10.1038/s41574-026-01243-y · Cited by 8 · see citing works
“183,184) or anti-TNF antibodies could reduce lymphatic permeability and avoid the weight gain associated with non-targeted inhibition of these cytokines 183 .”
Immunometabolism at the crossroads of obesity and cancer—a Keystone Symposia report
Cable, J., Rathmell, J. C., Pearce, E. L., Ho, P., Haigis, M. C., Mamedov, M. R., Wu, M., Kaech, S. M., Lynch, L., Febbraio, M. A., et al. (2023) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14976 · Cited by 6 · see citing works
“26,27 Lynch presented unpublished data looking at the impact of different types of high-fat diets on immune function and tumor growth.”
Chen, Q., Cai, W., Ni, Q., Lin, S., Jiang, C., Yi, Y., Liu, L., Liu, Q., & Shen, C. (2025) · Phytotherapy Research · doi:10.1002/ptr.8521 · Cited by 6 · see citing works
“Conversely, at normal levels, such as under exercise or pharmacological stimulation, IL-6 acted to enhance insulin sensitivity and activate BAT thermogenesis and liver fatty acid oxidation (Findeisen et al. 2019; Timper et al. 2017).”
Exerkines: Benign adaptation for exercise and benefits for non-alcoholic fatty liver disease
Chen, Y., Zhang, Y., Jin, X., Hong, S., & Tian, H. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150305 · Cited by 5 · see citing works
Designer cytokine for the treatment of diabetes
Donath, M. Y. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0130-z · Cited by 5 · see citing works
Dong, Q., Ai, J., Xiao, A., Wu, P., Wu, M., Liu, X., Huselstein, C., Cai, L., Feng, X., & Chen, Y. (2023) · ACS Omega · doi:10.1021/acsomega.3c00613 · Cited by 4 · see citing works
Al‐Rashed, F., AlSaeed, H., Almansour, N., Al‐Mulla, F., Hannun, Y. A., & Ahmad, R. (2024) · Clinical Immunology · doi:10.1016/j.clim.2024.110351 · Cited by 4 · see citing works
Advances in rationally engineered cytokines for precision therapy in diabetic wound healing
Zhang, X., Wang, T., Fan, X., Zhang, T., Qiu, R., Wu, Y., Wang, M., Zhang, Y., Li, M., Cai, N., et al. (2024) · Exploration of Immunology · doi:10.37349/ei.2024.00157 · Cited by 3 · see citing works
Designing a new therapy for T2DM
Greenhill, C. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0272-9 · Cited by 3 · see citing works
Bitsi, S. (2020) · Cytokine · doi:10.1016/j.cyto.2020.155154 · Cited by 3 · see citing works
Investigating plasticity within the interleukin-6 family with AlphaFold-Multimer
Düsterhöft, S., Greve, J. N., & Garbers, C. (2025) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2025.02.030 · Cited by 3 · see citing works
“Although their amino acid sequence is very different, cytokines and cytokine receptors of the IL-6 family have similar topologies and protein folds, which allows swapping of domains between receptors [21] and exchange of receptor binding sites between cytokines [22,23].”
Panhuis, W. I. H., Thiemann, E., van Dijk, D. M. A. H., Been, B., Jarrett, K. E., Meurs, A., Kooijman, S., Hovingh, M. V., Modder, M., van Os, B. W., et al. (2025) · Science Advances · doi:10.1126/sciadv.adx3794 · Cited by 2 · see citing works
“IC7Fc treatment improved glucose tolerance and hyperglycemia and prevented weight gain and liver steatosis in obese mice, while administration to human cells in vitro and nonhuman primates resulted in no signs of inflammation or immunogenicity ( 22 ).”
InfluentialStafeev, I., Yudaeva, A., Michurina, S. S., Menshikov, M. Y., Shestakova, M. V., & Parfyonova, Y. V. (2023) · Diabetes Mellitus · doi:10.14341/dm12982 · Cited by 2 · see citing works
Obesity-Associated Chronic Inflammation: A Protective Mechanism against Type 2 Diabetes
Ye, J. (2025) · Immune discovery. · doi:10.70322/immune.2025.10007 · Cited by 1 · see citing works
Concurrent management of gout and type 2 diabetes mellitus: combined therapy insights
Wang, H., Wang, B., Zhang, J., TONG, H., Arés, I., Martínez, M., López-Torres, B., Martínez‐Larrañaga, M., Pan, Y., Zhang, J., et al. (2026) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2026.113169 · Cited by 1 · see citing works
Tong, F., Chen, Y., Gui, H., Li, A., Li, H., Pei, Y., Wu, Z., & Wang, M. (2026) · Metabolites · doi:10.3390/metabo16080562 · Cited by 1 · see citing works
“Systemic therapeutic targeting is especially premature. gp130/LIFR signaling is pleiotropic; chronic exposure may trigger SOCS feedback, and the same ligand can have divergent muscle, neural, bone, adipose, immune, and cardiac effects [16,33,34,42,44,76–79].”
Building a designer cytokine to treat type 2 diabetes
Paiva, S.-L. (2019) · Nature Reviews Drug Discovery · doi:10.1038/d41573-019-00168-8 · Cited by 1 · see citing works
An Overview of Hypoglycemic Biological Drugs
Chen, H., & Wang, Q. (2021) · Springer eBooks · doi:10.1007/978-981-15-8791-7_3 · Cited by 1 · see citing works
Wang, F., Mi, J., Bai, X., Ruan, G., Zhang, Y., & Yu, K. (2022) · Research Square · doi:10.21203/rs.3.rs-1751879/v2 · Cited by 1 · see citing works
Faculty Opinions recommendation of Origin and Function of Stress-Induced IL-6 in Murine Models.
Lynch, L. (2021) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.738227474.793583818
Zhang, H., An, X., Jin, D., Tian, J., Liu, W., Zhao, S., Wang, X., Hu, Y., Lian, F., & Tong, X. (2021) · Research Square · doi:10.21203/rs.3.rs-147873/v1
Wang, F., Mi, J., Bai, X., Ruan, G., Zhang, Y., & Yu, K. (2022) · Research Square · doi:10.21203/rs.3.rs-1751879/v1
Lasso-grafted designer cytokines
Kapurniotu, A., & Bernhagen, J. (2022) · Nature Biomedical Engineering · doi:10.1038/s41551-022-00974-3
EXERCINAS: NOVOS HORIZONTES NA BIOLOGIA DO EXERCÍCIO FÍSICO
Yamada, A. K. (2023) · Revista Brasileira de Ciência e Movimento · doi:10.31501/rbcm.v30i3.12682
The Biology of Interleukin-6: A Major Target in Anti-Inflammatory Therapies
Rose‐John, S. (2024) · Elsevier eBooks · doi:10.1016/b978-0-128-24465-4.00103-4
Tang, X., Abbott, C. J., Allen, P. J., & Luu, C. D. (2025) · Documenta Ophthalmologica · doi:10.1007/s10633-025-10045-y
Wienbeuker, E., Felker, A., Nevskyi, O., Harms, S. T., Marx, D., Tanzusch, K., Chizhik, A. M., Kurre, R., You, C., Enderlein, J., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.23.719849
Tang, S., Zhu, L., Wu, X., Zhu, J., Liu, J., Gao, D., Xue, J., Shi, R., Pan, Y., Chen, X., et al. (2026) · Tissue and Cell · doi:10.1016/j.tice.2026.103871
Exerkines in precision management of metabolic diseases
Jin, L., Lin, Y., Zheng, Y., Wang, A., Liao, P., Luo, Y., Sui, Z., Ni, X., Zhang, J., Shen, Q., et al. (2026) · Chinese Medical Journal · doi:10.1097/cm9.0000000000004200
“[48] Myonectin promotes lipid clearance and oxidation.”
Engineering Protein Circuits for Cellular Control and Precision Immunotherapy
Spina, S. C., Bailey, J., Rajagopal, G., Phan, N., & Kimmel, B. R. (2026) · Chem & Bio Engineering · doi:10.1021/cbe.6c00083
- Authors
- Findeisen, M., Allen, T. L., Henstridge, D. C., Kammoun, H., Brandon, A. E., Baggio, L. L., Watt, K. I., Pal, M., Cron, L., Estevez, E., Yang, C., Kowalski, G. M., O’Reilly, L., Egan, C., Sun, E., Thai, L. M., Krippner, G., Adams, T. E., Lee, R. S., Grötzinger, J., Garbers, C., Risis, S., Kraakman, M. J., Mellet, N. A., Sligar, J., Kimber, E. T., Young, R. L., Cowley, M. A., Bruce, C. R., Meikle, P. J., Baldock, P. A., Gregorevic, P., Biden, T. J., Cooney, G. J., Keating, D. J., Drucker, D. J., Rose-John, S., & Febbraio, M. A.
- Affiliations
- Garvan Institute of Medical Research (AU)
- Baker Heart and Diabetes Institute (AU)
- The University of Sydney (AU)
- Mount Sinai Hospital (CA)
- The University of Melbourne (AU)
- Monash University (AU)
- Flinders University (AU)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- Christian-Albrechts-Universität zu Kiel (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
- The University of Adelaide (AU)
- Corresponding author
- Febbraio, Mark A.
- ORCID
- Findeisen, Maria
- Henstridge, Darren C.
- Brandon, Amanda E.
- Watt, Kevin I.
- Yang, Christine
- Kowalski, Greg M.
- O’Reilly, Liam
- Sun, Emily
- Thai, Le May
- Krippner, Guy
- Adams, Timothy E.
- Lee, Robert S.
- Garbers, Christoph
- Kraakman, Michael J.
- Mellet, Natalie A.
- Sligar, James
- Young, Richard L.
- Cowley, Michael A.
- Bruce, Clinton R.
- Meikle, Peter J.
- Gregorevic, Paul
- Biden, Trevor J.
- Cooney, Gregory J.
- Keating, Damien J.
- Drucker, Daniel J.
- Febbraio, Mark A.
- Venue
- Nature
- Published
- 2019-09-25
- Volume
- 574
- Issue
- 7776
- Pages
- 63-68
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2976069324
- Cited by
- 86
- References
- 41
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 12 · 2023: 13 · 2022: 15 · 2021: 15 · 2020: 11 · 2019: 3
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- green
- research.monash.edu
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Monash University Research Portal (Monash University) (submittedVersion, other-oa)
- UTAS Research Repository (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 877, SFB 841)
- State Government of Victoria
- Exzellenzclusters Entzündungsforschung
- Canadian Institutes of Health Research
- Medical Research Council
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- type 2 diabetes, cytokine engineering, gp130, interleukin-6, ciliary neurotrophic factor, LIF receptor, Fc fusion protein, glucose tolerance, hyperglycemia, hepatic steatosis, weight gain, skeletal muscle mass, muscle atrophy, YAP, immunogenicity, non-human primates
- MeSH terms
- YAP-Signaling Proteins, Interleukin-6 Inhibitors, Animals, Binding, Competitive, Diabetes Mellitus, Type 2, Fatty Liver, Glucose Tolerance Test, Humans, Hyperglycemia, Immunoglobulin G, Male, Obesity, Pancreas, Phosphoproteins, Recombinant Fusion Proteins, Transcription Factors, Drug Design, Protein Engineering, Signal Transduction, Weight Gain, Interleukin-6, Cytokines, Muscle, Skeletal, Receptors, Interleukin-6, Adaptor Proteins, Signal Transducing, Cytokine Receptor gp130, Mice, Incretins
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