Cellular & Molecular Metabolism
Our research is focused on identifying genes, proteins and pathways that are important in metabolic disease and certain types of obesity related cancer, and then to develop pharmaceutical therapies that either activate or block the pathway of interest. We currently have several drug candidates that we are exploring.
Together with N-Gene Pharmaceuticals, we have developed a drug (BGP-15) that has anti-inflammatory and anti-fibrotic properties. BGP-15 is currently in Phase 2B clinical trials for the treatment of type 2 diabetes, but has also shown efficacy in pre-clinical experiments for the treatment of Duchenne Muscular Dystrophy, Heart Failure, and non-alcoholic steatohepatitis (NASH) principally due to its anti-fibrotic effects.
Almost a decade ago, work from our lab showed that cytokines from the gp130 family of cytokines (IL-6 and CNTF) can protect against obesity and insulin resistance by activation of the fuel sensing kinase, AMPK. With our collaborator Professor Stefan Rose John at the University of Kiel, this led to the development of IC7, a designer cytokine which is a chimera of CNTF and IL-6. IC7 is showing promise as a drug to treat obesity and type 2 diabetes and we have recently commenced pre-clinical development. We hope to start first in human trials within 24 months.
Finally, together with the University of Kiel, we recently showed that a drug that can block IL-6 “trans-signalling” (sgp130Fc) can markedly prevent inflammation. Phase 1 human clinical trials for sgp130Fc have recently been completed and we are now focusing on the role of sgp130Fc for the treatment of Rheumatoid Arthritis, NASH and other diseases where inflammation and fibrosis are major mediators.
Significant findings include:
- Identification that muscle is an endocrine organ: IL-6 the first myokine
- Identification that activation of HSP72 can result in protection against insulin resistance
- Discovery that the mechanism of action of gp130 receptor ligands CNTF and IL-6 in protecting against obesity and insulin resistance is via the activation of skeletal muscle AMPK
- The chemical chaperone BGP-15 can improve the pathology and functional capacity of skeletal muscle in muscular dystrophy and cardiac muscle in heart failure
- Blocking IL-6 trans-signalling can prevent high fat diet-induced inflammation
The opposing effects of physical inactivity and exercise on disease risk (from Whitham & Febbraio, Nature Reviews Drug Discovery, 2016).
Current laboratory groups and projects
Project 1 Obesity, NASH & liver cancer
(Project leader Dr Ebru Boslem)
Hepatocellular carcinoma (HCC) is one of the most fatal and fastest growing cancers. In recent years, non-alcoholic steatohepatitis (NASH) has been recognized as a major HCC catalyst. However, it is difficult to decipher the molecular mechanisms underlying the pathogenesis of NASH and understand how it progresses to HCC by studying humans. Consequently, progress in this field depends on the availability of reliable preclinical models that are amenable to genetic and functional analyses and exhibit robust NASH to HCC progression. Together with our collaborators at UCSD, we have developed a mouse model of NASH driven HCC that mimics human disease. We are uncovering novel pathways and therapies to treat this condition.
Project 2 Nexus between ceramides, metabolism and inflammation
(Project leader Dr Sarah Turpin-Nolan)
Ceramide accumulation represents a hallmark in the manifestation of numerous obesity-associated diseases such as type 2 diabetes mellitus and atherosclerosis. Until recently, ceramides were viewed as a homogenous class of sphingolipids. However, it has now become clear that ceramides exert fundamentally different effects depending on the specific fatty acyl-chain lengths that are integrated into ceramides by a group of enzymes known as (dihydro)ceramide synthases (CerS), as exemplified by distinct phenotypes of CerS-deficient mice. In addition, alterations of ceramide synthesis, trafficking and metabolism in specific cellular compartments exert distinct consequences on metabolic homeostasis. We are examining the emerging concept of how the intracellular location of acyl-chain length ceramides can regulate glucose metabolism, thus emphasising their targeting potential in the development of novel and specific therapies for obesity and obesity-associated diseases.
Role of ceramides in metabolic disease (from Turpin et al Cell Metabolism, 2014).
Project 3 Developing novel chimeric cytokine proteins for the treatment of metabolic disease (Project leader Prof Mark Febbraio)
IC7 is a novel chimeric cytokine that protects against metabolic disease (from Findeisen et al Nature, 2019)
Previous work from our laboratory demonstrated that the gp130 receptor cytokines interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) can improve metabolic disease, but due to the known pro-inflammatory effects of IL-6 and the antigenic response to the clinically used form of CNTF (AxokineTM), both proteins were shown to have limited therapeutic utility for treatment of type 2 diabetes (T2D). Accordingly, we are engineering novel chimeric gp130 ligands to treat metabolic disease. We have shown that some of these new proteins significantly improve glucose tolerance and hyperglycemia and prevent weight gain and liver steatosis in both obese mice and in non-human primates. We hope to develop a realistic next-generation biological for the treatment of obesity, T2D, and age-associated sarcopenia, disorders that are currently pandemic.
Project 4 Development of novel drugs to treat age-related diseases
(Project leader Dr Peter Keov)
Together with N-Gene Pharmaceuticals, our group has been involved in the development of the small molecule named BGP-15, which is currently in two separate Phase 2 clinical trials for the treatment of type 2 diabetes (T2D) and idiopathic cardiomyopathy respectively. The drug has been shown to be extremely safe in five previous human intervention studies. We have demonstrated BGP-15 to be effective in treating a variety of pathologies including type 2 diabetes, muscular dystrophy, heart disease, and in the restoration of oocyte quality and embryo development. Our research indicates that BGP-15 is a promising drug for conditions in which mitochondrial function is impaired such as age-related sarcopenia. Mitochondrial function declines with age and is thought to contribute to many diseases associated with aging. Therefore, any therapeutic target that could improve the quality of life of aged Australians would have an enormous social and economic benefit for our country.
BGP-15 is antifibrotic and improves the pathology and lifespan of mice with muscular dystrophy (from Gehrig et al Nature 2012).
Project 5 Role of exercise and exosomes in age-related diseases
(Project leader Prof Mark Febbraio)
Small vesicles are released into the circulation with exercise, and participate in tissue cross-talk to prevent disease progression (from Whitham et al Cell Metabolism 2018).
Exercise represents a highly complex perturbation of homeostasis in a wide number of tissues, largely consequential of the increasing metabolic demands of contracting skeletal muscle. The integrated responses to these demands not only restore homeostasis in the short term, but when challenged regularly, produce adaptations associated with improved health and wellbeing. Indeed, poor exercise capacity is the most powerful predictor of mortality and there is evidence for the prescription of exercise as therapy for musculoskeletal, metabolic, cardiovascular, neurological and pulmonary diseases, as well as some cancers. Despite this, the mechanisms behind the therapeutic effects of exercise are not well understood and seem to go beyond simple management of energy balance and body weight. Over 15 years ago, we demonstrated that the pleiotropic cytokine interleukin-6 (IL-6) is released from skeletal muscle during exercise, resulting in the inception of the ‘myokine’ concept, that skeletal muscle functions as an endocrine organ. Inspired by the growing recognition that proteins can circulate packaged in extracellular vesicles (EV), we have taken the innovative approach of screening plasma taken from humans after exercise, focussing entirely on the EV fraction. We, therefore, have preliminary evidence describing an entirely novel mechanism by which tissue cross-talk occurs with exercise, that being via newly released exosomes. Accordingly, we have potentially uncovered an intriguing pathway by which exercise exerts its protective effects against many diseases including Alzheimer’s disease, liver disease and breast cancer.
Findeisen M, Allen TL, Henstridge DC, Kammoun H, Brandon AE, Baggio LL, Watt KI, Pal M, Cron L, Estevez E, Yang C, Kowalski GM, O'Reilly L, Egan C, Sun E, Thai LM, Krippner G, Adams TE, Lee RS, Grötzinger J, Garbers C, Risis S, Kraakman MJ, Mellet NA, Sligar J, Kimber ET, Young RL, Cowley MA, Bruce CR, Meikle PJ, Baldock PA, Gregorevic P, Biden TJ, Cooney GJ, Keating DJ, Drucker DJ, Rose-John S, Febbraio MA. Treatment of type 2 diabetes with the designer cytokine IC7Fc. Nature 574: 63-68, 2019.
Febbraio MA, Reibe S, Shalapour S, Ooi G, Watt MJ, Karin M. Pre-clinical models for studying NASH driven HCC: how useful are they? Cell Metab 29:18-26, 2019.
Turpin-Nolan SM, Hammerschmidt P, Chen W, Jais A, Timper K, Awazawa M, Brodesser S and Brüning JC. CerS1-derived C18:0 ceramide in skeletal muscle promotes obesity-induced insulin resistance. Cell Reports, 26(1):1-10.e7, 2019.
Lindegaard B, Abilgaard J, Heywood SE, Pedersen BK, Febbraio MA. Role of Interleukin-18 in the maintenance of metabolic homeostasis is influenced by female sex hormones. Mol Metab 12: 89-97, 2018
Lancaster GI, Langley KG, Anton Berglund N, Kammoun HL, Reibe S, Estevez E, Weir J, Mallett NA, Pernes G, Conway JRW, Lee MK, Timpson P, Murphy AJ, Masters SL, Gerondakis S, Bartonicek N, Kaczorowski DC, Dinger ME, Meikle PJ, Bond PJ, Febbraio MA. TLR4 is not a receptor for saturated fatty acids but mediates lipid-induced inflammation by re-programming macrophage metabolism. Cell Metab 27: 1096-1110, 2018.
Kammoun HL, Allen TL, Henstridge DC, Barre S, Coll R, Cron L, Reibe S, Murphy AJ, Bensellam, M, Laybutt R, Butler MS, Robertson AB, O’Neill LA, Cooper MA, Febbraio MA. Evidence against a role for NLRP3-driven inflammation in db/db mice. Mol Metab 10: 66-73, 2018.
Whitham M, Parker BL, Friedrichsen M, Hingst JR, Hjorth M, Hughes WE, Egan CL, Cron LNN, Watt KI, Kuchel RP, Jayasooriah N, Estevez E, Petzold T, Suter CM, Gregorevic P, Kiens B, Richter EA, James DE, Wojtaszewski JFP, Febbraio MA. Extracellular vesicles provide a means for tissue cross talk during exercise. Cell Metab 27: 237-251, 2018.
Man K, Liao Y, Gabriel S, Gloury R, Preston S, Henstridge DC, Marc Pellegrini M, Berberich-Siebelt F, Febbraio MA, Shi W, Kallies A. Transcription factor IRF4 promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity 47: 1129-1141, 2017.
Lee-Young RS, Hoffman N, Murphy KT, Henstridge DC, Iliades P, Zivanovic B, Hong YH, Colgan T, Kraakman MJ, Bruce CR, Gregorevic P, Kingwell BA, McConell GK, Wadley GD, Lynch GS, Drummond GR, Febbraio MA. Glucose-6-phosphate dehydrogenase activity contributes to the regulation of glucose uptake in skeletal muscle. Mol Metab. 5: 1083-1091, 2016.
Lancaster GI, Kammoun KL, Kraakman MJ, Kowalski GM, Bruce CR, Febbraio MA. PKR is not obligatory for high fat diet-induced obesity and its associated metabolic and inflammatory complications. Nature Comm. 7: 10626 doi:10.1038/ncomms10626), 2016.
Murphy AJ, Kraakman MJ, Lawlor KE, Wentworth JM, Vasanthakumar A, Gerlic M, DiRago L, Cengia L, Metcalf D, Roberts AW, Vince JE, Harrison LC, Kallies A, Kile BT, Croker BA, Febbraio MA, Masters SL. IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome. Cell Metab. 23: 155-164, 2016
Selathurai A, Burch ML, Kowalski GM, Sepulveda P, Risis S, Lee-Young RS, Meikle PJ, Genders AJ, McGee SL, Watt MJ, Russell AP, Frank M, Jackowski S, Febbraio MA, Bruce CR. Elimination of the CDP-ethanolamine pathway in skeletal muscle has pronounced effects on lipid homeostasis and mitochondrial oxidative capacity without altering insulin sensitivity. Cell Metab. 21: 718-730, 2015.
Kraakman MJ, Kammoun HL, Allen TL, Deswaerte V, Henstridge DC, Estevez E, Matthews VB, Neill B, White DA, Murphy AJ, Peijs L, Yang C, Rises S, Bruce CR, Du X-J, Bobik A, Lee-Young RS, Kingwell BA, Vasanthakumar A, Shi W, Kallies A, Lancaster GI, Rose-John S, & Febbraio MA. Blocking IL-6 trans-signaling prevents high fat diet-induced adipose tissue macrophage recruitment and does not exacerbate weight gain, liver steatosis or insulin resistance. Cell Metab 21: 403-416, 2015.
Sapra G, Tham YK, Cemerlang N, Matsumoto A, Kiriazis H, Bernardo BC, Henstridge DC, Ooi JYY, Pretorius L, Boey EJH, Lim L, Sadoshima J, Meikle PJ, Mellet NA, Woodcock EA, Marasco S, Ueyama T, Dy X-J, Febbraio MA*, & McMullen JR*. The small molecule, BGP-15, protects against heart failure and atrial fibrillation in mice. Nature Comm. DOI: 10.1038/ncomms6705, 2014.
Henstridge DC, Bruce CR, Tory K, Kolonics A, Drew BG, Chung J, Watson N, Estevez E, Gardner T, Lee-Young RS, Connor T, Watt MJ, Hargreaves M, McGee SL, Hevener AL, & Febbraio MA. Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance. Diabetes 63: 1881-1894, 2014.
Turpin SM, Nicholls HT, Willmes DM, Mourier A, Brodesser S, Hammerschmidt P, Wunderlich C, Mauer J, Xu E, Brönneke H, Trifunicnovic A, LoSasso G, Wunderlich FT, Kornfeld JW, Blüher M, Krönke M and Brüning JC. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab, 20:678-86, 2014.
Mauer J, Chaurasia B, Goldau J, Vogt MC, Schmitz J, Ruud J, Nguyen KD, Theuric S, Hausen C, Bronneke HS, Estevez, E, Allen TL, Febbraio MA, Chawla A, Wunderlich FT, & Brüning JC. IL-6 signaling in myeloid cells promotes alternative macrophage activation to limit obesity-associated insulin resistance. Nature Immunol. 15: 423-430, 2014.
Man, K, Miasari M, Shi W, Xin A, Henstridge DC, Preston S, Pellegrini M, Belz GT, Smyth GK, Febbraio MA, Nutt SL, & Kallies A. IRF4 is essential for T cell receptor affinity mediated metabolic programming and clonal expansion of T cells. Nature Immunol 14: 1155-1165, 2013.
Lindegaard B, Matthews VB, Brandt C, Hojman P, Allen TL, Estevez E, Watt MJ, Bruce CR, Mortensen O, Syberg S, Rudnicka C, Abildgaard J, Pilegaard H, Hidalgo J, Ditlevsen S, Algreen T, Madsen AN, Pedersen BK, & Febbraio MA. Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice. Diabetes 62: 3064-3074, 2013.
Teperino R, Amann S, Bayer M, McGee SL, Loipetzberger A, Conner T, Jaeger C, Kammerer B, Winter W, Wiche G, Dalgaard K, Riter J, Gaster M, Lee Young R, Febbraio MA, Knauf C, Cani PD, Aberger F, Penninger JM, Pospisilik JA, & Esterbauer H. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell 151: 414-426, 2012.
Bruce CR, Risis S, Babb JR, Yang C, Kowalski GM, Selathurai A, Lee-Young RS, Wier JM, Yoshioka K, Takuwa Y, Meikle PJ, Pitson SM, & Febbraio MA. Overexpression of sphingosine kinase 1 prevents ceramide accumulation and ameliorates muscle insulin resistance in high fat fed mice. Diabetes 61: 3148-3155, 2012.
Gehrig S, van der Poel C, Sayer TA, Schertzer JD, Henstridge DC, Church JE, Lamon S, Russell AP, Davies KE, Febbraio MA, & Lynch GS. HSP72 preserves muscle function and slows progression of severe muscular dystrophy. Nature 484: 384-398, 2012.
Whitham M, Chan MHS, Matthews VB, Prelovsek O, Lunke S, El-Osta A, Wunderlich FT, Pal M, Broenneke H, Bruning J, Lancaster GI, & Febbraio MA. Contraction-induced IL-6 gene transcription in skeletal muscle is regulated by c-jun terminal kinase/Activator protein -1. J Biol. Chem. 287: 10771-10779, 2012.
Nicholls HT, Kowalski G, Risis S, Zaffino LA, Watson N, Kanellakis P, Watt MJ, Bobik A, Bonen A, Febbraio M, Lancaster GI, & Febbraio MA. Haematopoietic cell restricted deletion of CD36 reduces high fat diet-induced macrophage infiltration and insulin resistance in adipose tissue. Diabetes 60:1100-1110, 2011.
Matthews VB, Allen TL, Risis S, Chan MHS, Watson N, Zaffino LA, Babb J, Boon J, Meikle PJ, Jowett J, Watt MJ, Jannson J-O, Bruce CR, & Febbraio MA. Interleukin-6 deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia 53: 2431-2441, 2010.
Yuen DYC, Dwyer RM, Matthews VB, Drew BG, Southgate RJ, Neill B, Kingwell BA, Clark MG, Rattigan S, & Febbraio MA. IL-6 attenuates insulin mediated increases in endothelial cell signaling, but augments skeletal muscle insulin action via differential effects on TNF-α expression. Diabetes 58:1086–1095, 2009.
Chung J, Nguyen A-K, Henstridge DC, Holmes AG, Chan MHS, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy S, Vigh L, Horvath I, Mestril R, Watt MJ, Hooper PD, Kingwell BA, Hevener A, & Febbraio MA. HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci USA 105: 1739-1744, 2008.
Steinberg GR, Michell BJ, van Denderen B, Watt MJ, Fam BC, Andrikopoulos S, Gorgun CZ, Proietto J, Carling D, Hotamisligil, GS, Febbraio MA, Kay, TW, & Kemp BE. Tumor necrosis factor-α induced skeletal muscle insulin resistance involves the suppression of AMP-kinase signaling. Cell Metab 4: 465-474, 2006.
Carey AL, Steinberg GR, Macaulay SL, Thomas WJ, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, Kemp BE, Petersen BK, & Febbraio MA. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55: 2688-2697, 2006.
Watt MJ, Dzamko N, Thomas W, Rose-John S, Ernst M, Carling D, Kemp BE, Febbraio MA. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nature Med 12: 541-548, 2006. Accompanied by Research Highlight: Ahima RS. Overcoming insulin resistance with CNTF Nature Med. 12, 511-512, 2006.
Reibe S,Febbraio MA. Relieving ER-stress to target NASH driven Hepatocellular Carcinoma Nat. Rev Endocrinol. 15: 72-74, 2019.
Hjorth M, Febbraio MA. Exercise as medicine for survivors of paediatric cancer. Nat. Rev Endocrinol. 14:506-508, 2018.
Whitham M, Febbraio MA. The ever expanding myokinome: discovery challenges and therapeutic implications. Nature Rev. Drug Discov. 15: 719-729, 2016.
Lancaster GI, & Febbraio MA. The immune-modulating role of exercise in metabolic disease. Trends Immunol 35:262-269, 2014.
Febbraio MA. Role of interleukins in energy homeostasis: implications for metabolic disease. Trends Endocrinol & Metab 25: 312-319, 2014.
Pedersen BK, & Febbraio MA. Muscle, exercise and obesity: skeletal muscle as a secretory organ. Nature Rev Endocrinol. 8: 457-465, 2012.
Pedersen BK, & Febbraio MA. Muscle as an endocrine organ – focus on muscle-derived IL-6. Physiol. Rev. 88: 1379-1406, 2008.
Febbraio MA. gp130 receptor ligands: potential therapeutic targets in obesity J. Clin Invest. 117: 841-849, 2007.
- Dr Sarah Turpin-Nolan
- Dr Ebru Boslem
- Dr Peter Keov
- Dr Benoit Smeuninx
- Emma McLennan
- Surafel Tegegne
- Casey Egan
- Oliver Fuller (PhD candidate)
- Prof Michael Karin (UCSD)
- Prof Stefan Rose-John (University of Kiel)
- Prof Bente Pedersen (University of Copenhagen)
- Dr Martin Whitham (University of Birmingham)
- Prof Nicholas Shackel (UNSW)
- Prof Axel Kallies (University of Melbourne)
- A/Prof Julie McMullen (Baker Heart & Diabetes Institute)
- Dr John O’Sullivan (University of Sydney)
- Dr David Gallego-Ortega (Garvan Institute of Medical Research)
- Dr Timothy Adams (CSIRO)
Febbraio MA. "A Novel Therapy for the Treatment of Alzheimer’s Disease." The Yulgilbar Alzheimer’s Research Program
Febbraio MA. Senior Principal Research Fellow of the National Health & Medical Research Council
Febbraio MA, Karin M, Shackel N. "NAFLD and Hepatocellular Carcinoma: Mechanisms & Potential Treatments." National Health & Medical Research Council Project Grant
McMullen J, Febbraio MA, White M, Carey A. “Identification of novel secretory factors from the heart as new targets for metabolic disease.” National Health & Medical Research Council Project Grant
Febbraio MA, Rose-John S. “The designer cytokine IC7: a novel therapy for the treatment of type 2 diabetes.” National Health & Medical Research Council Project Grant