Cellular and Molecular Metabolism

- Staff of the Cellular and Molecular Metabolism laboratoryProfessor Mark Febbraio
Program Head: Metabolism and Inflammation
Head, Cellular and Molecular Metabolism Laboratory
NHMRC Senior Principal Research Fellow
mark.febbraio@bakeridi.edu.au
Phone: +61 3 8532 1767
Mobile: +61 402 363 194

 

 

Research Overview 

Professor Mark Febbraio and his team are at the forefront of research into the metabolic changes that leads to type 2 diabetes. Diabetes is a serious public health issue and its dramatic rise in the community is a major social and economic burden.

Our research is focused on identifying genes/proteins that are important in pathways that may impair insulin action and then to develop pharmaceutical therapies that either activate or block the pathway of interest. We currently have two such candidates. Together with N-Gene Pharmaceuticals we have developed a drug (BGP-15) currently in a multi-centre clinical trial for type 2 diabetes. In addition, in a paper published in 2012, we showed that this drug has pre-clinical efficacy for the treatment of Duchenne muscular dystrophy and we are about to commence human clinical trials in this disease. In addition, based on our previous work targeting the IL-6 family of cytokines, we have developed another peptide in pre-clinical development. Our research includes cell based experiments, pre-clinical experiments in diet-induced or genetically obese rodents and clinical human experimentation. Our work is well regarded with papers published in journals such as Nature, Cell, Nature Medicine, Cell Metabolism, Journal of Clinical Investigation, Proceedings of the National Academy of Sciences USA, Diabetes and Diabetologia. We are funded through multiple grants from the National Health and Medical Research Council of Australia and the Australian Research Council.

Research Focus

Significant findings include:

  • Discovery that muscle is an endocrine organ with the identification of the first myokine interleukin-6 (see Febbraio et al., Diabetes 2004; Pedersen & Febbraio, Physiol Rev. 2008; Pedersen & Febbraio, Nat. Rev. Endocrinol. 2012)
  • Identification that activation of HSP72 can result in protection against insulin resistance (see Chung et al., Proc Natl Acad Sci USA, 2008)
  • 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 (see Carey et al., Diabetes, 2006; Watt et al., Nat. Med, 2006, Febbraio, J Clin Invest, 2007).
  • Discovery that activation of HSP72 can improve the pathology and functional capacity of skeletal muscle in muscular dystrophy (see Gehrig et al., Nature 2012).

Research Projects

Inflammation and insulin resistance

Group leader: Dr Graeme Lancaster

In the past fifteen years it has become apparent that hyperlipidemia, a hallmark of obesity, is linked to a state of chronic inflammation. Somehow, lipid-induced inflammation results in the the activation of key serine threonine kinases namely c-jun amino terminal kinase (JNK) and inhibitor of κB kinase (IKK) in insulin responsive tissues such as adipose tissue, skeletal muscle and liver. It is known that activation of both JNK and IKK disrupt insulin signalling and cause insulin resistance. It is thought that the mechanisms linking lipid oversupply to inflammation involves increased deposition of lipid species which are known to activate JNK and IKK in liver and/or skeletal muscle leading to insulin resistance. However, the precise molecular mechanisms linking these lipid species to upregulation of JNK and IKK and ultimately impaired insulin action are not fully resolved. We have several projects in this group aimed at resolving the role of inflammation in insulin resistance.

Discovery of novel myokines 

Group leader: Dr Martin Whitham

Skeletal muscle is primarily known as an organ of locomotion. Large bodies of evidence characterise the mechanistic, metabolic and morphological properties of skeletal muscle from the perspective of providing movement and locomotion in various species. However, in recent years, our laboratory has identified skeletal muscle as a cytokine-producing organ, suggesting an endocrine role for skeletal muscle in stress states such as exercise. While there is an expanding array of myokines, the discovery of the majority of these candidates have been made somewhat serendipitously, using assays targeted to these proteins and subsequent deduction of the cellular origin of release. It is anticipated that a model that could screen the proteome released from contracting muscle would identify more biologically relevant myokines. The aim of this project is to therefore identify novel myokines through the innovative use of isotopic labeling and tandem mass spectrometry. We hypothesise that we will uncover novel myokine candidates that may, in the long term, have implications for human health and preventative healthcare.

- Febbraio - Myokinome

The "myokinome" in 2012. Current known myokines with known biological functions (from Pedersen BK, Febbraio MA, Nat Rev Endocrinol, 2012).

Role of heat shock protein 72 in health and disease 

Group leaders: Dr Darren Henstridge (HSP72 and mitochondria) and Professor Mark Febbraio (HSP72 and Duchenne muscular dystrophy)

In 2008, our group made the discovery that over-expression or activation of heat shock protein 72 (HSP72; the inducible form of the 70kDa family of heat shock proteins) in skeletal muscle reduces obesity-induced insulin resistance. These findings led to the development of the small molecule activator of HSP72, namely BGP-15, which was shown to be effective in proof of principal human clinical trials to treat type 2 diabetes and is now currently in a Phase 2b multicentre clinical trial. While we originally ascribed the mechanism of action of HSP72 in skeletal muscle to blocking inflammatory signalling cascades, we now have a evidence suggesting that increasing HSP72 in skeletal muscle increases oxidative capacity and mitochondrial number and function. These new data are exciting as they suggest that HSP72 may be a therapeutic target for not only type 2 diabetes, but for conditions in which mitochondrial function is impaired. Accordingly, this project examines whether activation of HSP72, using a drug with an excellent safety profile and good tolerability in humans, will lead to improvements in mitochondrial function and capacity, particularly in the context of type 2 diabetes and aging.

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder that affects ~1 in 3,500 live born males from early childhood. The disease is progressive and eventually affects all muscles, such that patients become dependent on a wheelchair, usually before their teens, and have only 25% of the muscle mass of healthy children. The progressive muscle wasting leads to premature death from respiratory or cardiac failure. At present there is no cure for DMD, and existing therapies are ineffective.

In a landmark pre-clinical study conducted in conjunction with Professor Gordon Lynch and co-workers at the University of Melbourne, we demonstrated that activation of HSP72 preserved the function of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump under conditions of cellular stress and in doing so, slowed the progression of muscular dystrophy. More important, however, was our observation that our drug BGP-15, was effective in improving disease pathology in two mouse models of DMD (see figure). We now intend to take our studies into human clinical trials.

- Febbraio - dko

Treatment of severely dystrophic (dko) mice with BGP-15 decreases kyphosis (spinal curvature), improves muscle function and prolongs lifespan (from Gehrig et al., Nature, 2012).

Targeting gp130 to prevent inflammation and promote insulin action 

Group leaders: Dr Tamara Allen (IC7 project) and Professor Mark Febbraio (gp130Fc project)

Over the past decade work from our group has demonstrated that the gp130 receptor cytokines, ciliary neurotrophic factor (CNTF) and interleukin-6 (IL-6), enhance fat oxidation in skeletal muscle and increase insulin sensitivity in vivo, principally via the activation of AMP activated protein kinase (AMPK). These results have generated a great deal of excitement as gp130 receptor ligands are now becoming recognised as a potential therapeutic target for obesity-induced insulin resistance. Together with Professor Stefan Rose John from the University of Kiel in Germany, we have synthesized a novel protein by transferring the putative "LIF receptor (LIFR) binding module" from CNTF to IL-6. We have shown that this new cytokine, termed IC7, has similar positive metabolic effects as CNTF, but may overcome the negative effects experienced by a variant of CNTF when in clinical trials. The aim of this project is to examine the efficacy of IC7 as a treatment strategy for obesity-induced insulin resistance and type 2 diabetes in a pre-clinical experimental model. Also in collaboration with Professor Rose John, we have developed a transgenic mouse that overexpresses the soluble form of the transmembrane receptor gp130 (sgp130Fc) which specifically blocks all interleukin-6 (IL-6) responses mediated by the soluble IL-6 receptor, but does not affect IL-6 responses via the membrane bound IL6R. In these mice, high fat diet induced macrophage recruitment to adipose tissue is blocked. In addition, we have found that administration of a soluble gp130Fc protein can prevent liver inflammation. Together, these preliminary observations strongly argue that blocking soluble IL-6R signalling is a viable therapeutic strategy for inflammation mediated metabolic disorders such as insulin resistance and non-alcoholic fatty liver disease (NAFLD). Thus, the aims of this project are to examine the efficacy of sgp130Fc as novel therapeutic strategy for the treatment of obesity-induced insulin resistance and NAFLD in preclinical experiments. Should this project be successful, it would be a major clinical advancement in the treatment of inflammation-induced metabolic disorders.

- Febbraio - IC7

IC7 is created by swapping the site III gp130 binding motif from IL-6 with the LIFR binding motif of CNTF. IC7 binds IL-6R and dimerises gp130 and LIFR.

Role of AMP-activated protein kinase (AMPK) and neuronal nitric oxide synthase (nNOSµ) in skeletal muscle metabolism

Group leader: Dr Robert Lee-Young

While a hallmark of skeletal muscle insulin resistance is a reduction in insulin-stimulated glucose uptake, the cellular fate of glucose is also altered, with less glucose being stored as glycogen and more glucose being oxidised. Likewise, while exercise is an effective adjunct treatment for obesity and Type 2 diabetes, these metabolic disease states are characterised by reduced exercise tolerance, and thus adherence to exercise is low. Obesity and Type 2 diabetes are characterised by reduced nNOSµ in skeletal muscle, a phenomenon associated with reduced glycogen synthesis, muscle perfusion, and mitochondrial function. AMPKα2 interacts with nNOSµ, and we and others have shown that obesity impairs AMPKα2 activity. Lean otherwise healthy mice expressing a kinase-dead AMPKα2 in skeletal muscle (KD) have reduced nNOSµ expression, and that HF fed wild-type mice have reduced AMPKα2 activity and nNOSµ activity in skeletal muscle. We have also shown that these two animal models have enhanced glucose oxidation and reduced glycogen deposition during an insulin clamp, and defects in exercise stimulated skeletal muscle glucose metabolism which lead to reduced exercise tolerance. We believe that these impairments stem from reduced nNOSµ expression. The aim of this project is to define the role of nNOSµ in the regulation of skeletal muscle glucose uptake and metabolism in healthy and obese, insulin resistant states in vivo.

Lab Head Profile

Professor Mark Febbraio is a Senior Principal Research Fellow of the NHMRC, is the head of the Cellular and Molecular Metabolism Laboratory at the Baker IDI Heart and Diabetes Institute. He is also the Chief Scientific Officer and on the Board of Directors of N-Gene Research Laboratories Inc., a USA based Biotechnology Company. His research is focussed on understanding cellular and molecular mechanisms associated obesity and type 2 diabetes. He has authored over 180 peer reviewed papers in leading journals such as Nature, Nature Medicine, Cell, Cell Metabolism, The Journal of Clinical Investigation, PNAS and Diabetes. His work is extremely well cited (~10,000 citations, H factor over 60). He has won prizes at international, national and institutional levels including the AK McIntyre Prize for significant contributions to Australian Physiological Science (1999), the Colin I Johnson Lectureship by the High Blood Pressure Research Council of Australia (2006), the ESA/ADS Joint Plenary Lecture (2009) and the Sandford Skinner Oration (2011). He is on the Editorial Board of Diabetes, American Journal of Physiology - Endocrinology & Metabolism, Exercise Immunology Reviews and Journal of Applied Physiology. He is a member of seven national or international professional bodies. He has served on the council of the Australian Diabetes Society and is a past Honorary Treasurer of this society (2006-2008). He has served on National Health and Medical Research Grant Review Panels for several years in the areas of Physiology, Cell Biology and Diabetes/Obesity. Professor Febbraio is also dedicated to health and fitness and continues to complete in running races and multi-sport events.

Major Achievements

1999 - AK McIntyre Medal, Australian Physiological Society
2000 - New Investigator Award, International Biochemistry of Exercise Conference, USA
2006 - Colin I Johnson Keynote Lecture, High Blood Pressure Research Council of Australia
2009 - Endocrine Society Australia/Australian Diabetes Society Joint Plenary Lecturer
2011 - Barbara Ell Lecturer, Victor Chang Cardiac Research Institute
2011 - The Sandford Skinner Oration Lecture, University of Melbourne
2011 - Faculty Member Leadership Victoria: Williamson Community Leadership Program
2012 - NHMRC Ten of The Best Research Grants
2013 - The Bosch Distinguished Seminar Speaker

Publication Highlights

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 2012;61:3148-55.

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 agaonism drives Warburg-like metabolism in muscle and brown fat. Cell 2012;151:414-26.

Pedersen BK, Febbraio MA. Muscle, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 2012;8:457-65.

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 2012;484:384-98.

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 2012;287:10771-9.

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 2011;60:1100-10.

Loh K, Deng H, Fukushima A, Cai X, Boivin B, Galic S, Bruce CR, Shields BJ, Skiba B, Ooms LM, Stepto N, Wu B, Mitchell CA, Watt MJ, Tonks N, Febbraio MA, Crack PJ, Andrikopoulos S, Tiganis T. Reactive oxygen species enhance insulin sensitivity. Cell Metab 2009;10:260-71.

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 2009;58:1086-95.

Pedersen BK, Febbraio MA. Muscle as an endocrine organ - focus on muscle-derived IL-6. Physiol Rev 2008;88:1379-406.

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 2008;105:1739-44.

Febbraio MA. gp130 receptor ligands: potential therapeutic targets in obesity J Clin Invest 2007;117:841-9.

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 2006;55: 2688-97.

Watt MJ, Dzamko N, Thomas W, Rose-John S, Ernst M, Carling D, Kemp BE, Febbraio MA, Steinberg G. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med 2006;12:541-8.

Lancaster GI, Febbraio MA. Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem 2005;280:23349-55.

Febbraio MA, Hiscock N, Sacchetti M, Fischer CP, Pedersen BK. Interleukin-6 is a novel factor mediating glucose homeostasis in skeletal muscle contraction. Diabetes 2004;53:1643-8.

Hiscock N, Chan MH, Bisucci T, Darby IA, Febbraio MA. Skeletal myocytes are the source of Interleukin-6 mRNA expression and protein release during contraction: evidence of fiber type specificity. FASEB J 2004;18:992-4.

Bruce CR, Carey AL, Hawley JA, Febbraio MA. Intramuscular HSP72 and HO-1 mRNA are reduced in patients with type 2 diabetes: evidence that insulin resistance is associated with a disturbed anti-oxidant defense mechanism. Diabetes 2003;52:2338-45.

Current Research Support (2013 funding)

2011-2013 Febbraio MA, Bruce CR, McGee S, Hargreaves M. Activation of HSP72 as a therapeutic target for obesity. NHMRC Project Grant- $212,000 per annum

2011-2013 Febbraio MA. An essential role for skeletal muscle FoxO1 in protecting against obesity-induced insulin resistance. NHMRC Project Grant- $190,000 per annum

2011-2013 Bruce CR, Febbraio MA. The CDP ethanolamine pathway: a new player in obesity-induced insulin resistance. NHMRC Project Grant- $189,000 per annum

2012-2016 Febbraio MA. NHMRC Senior Principal Research Fellow- $160,000 per annum

2012-2013 Febbraio MA, Adams T, Cowley MA. Development of a modified gp130 ligand to treat obesity-induced insulin resistance. NHMRC Development Grant- $212,000 per annum.

2013-2015 Febbraio MA. Blocking IL-6 trans-signalling: a therapeutic strategy to prevent metabolic disease. NHMRC Project Grant- $174,000 per annum

2013-2015 Febbraio MA. IC7: a gp130 receptor ligand to treat type 2 diabetes. NHMRC Project Grant- $193,000 per annum

2013-2015 Febbraio MA. Discovery of novel myokines by innovative proteomic analyses. ARC Discovery Project Grant- $115,000 per annum

Staff

Postdoctoral Fellows
Dr Graham Lancaster
Dr Robert Lee-Young
Dr Tamara Allen
Dr Martin Whitham
Dr Darren Henstridge
Dr Helene Kammoun
Dr Emma Estevez
Dr Peter Illiadis
Dr Martin Pal

Research Assistants
Christine Yang
Saskia Pal

Students
Michael Kraakman (PhD)
Katherine Langley (PhD)

 

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Download a publications list here