Metabolism and Obesity

Professor Mark Febbraio
Head, Cellular and Molecular Motabolism
mark.febbraio@bakeridi.edu.au

Laboratory 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. The complications of diabetes include kidney disease, eye disease and vascular disease. Diabetes is a major factor in cardiovascular disease and the most common cause of kidney failure in the western world.

In 2000 his lab, in collaboration with Danish researchers, made the pivotal discovery that the cytokine IL-6 is synthesised and then secreted from skeletal muscle to modulate metabolic processes. In effect, they discovered that skeletal muscle is an endocrine organ capable of secreting molecules known as “myokines”. This discovery laid the foundation for work published in Nature Medicine in 2006, that showed that ciliary neurotrophic factor (CNTF), another member of the IL-6 family of cytokines, prevents obesity and insulin resistance. In collaboration with researchers from St Vincents Institute of Medical Research in Melbourne Australia, the group found that obesity and insulin resistance was prevented in mice that were fed a high fat diet but administered CNTF. The group is now working on designer cytokines that activate the IL-6 receptor as potential therapies to combat obesity.

In different studies, Mark’s group have identified a novel pathway that protects against, inflammation, obesity and insulin resistance. In work published early this year in the Proceedings of the National Academy of Sciences USA, the group identified that a specific chaperone protein, namely heat shock protein 70 (HSP70) prevented obesity-induced insulin resistance. The group now plans to take a small molecule activator of HSP70 into human clinical trials.

Mark and his team aim to continue research that will have effects beyond the scientific community and directly improve the health of Australians and reverse the rise of lifestyle disorders by investigating the molecular basis of obesity, diabetes and related disorders.

Research Focus

The team's research focus is on the development of drugs that will target obesity and obesity-induced inflammation. Some of these are related to mimicking the effects of exercise. As head of Baker IDI's Cellular and Molecular Metabolism laboratory, Mark conducts research into a condition known as insulin resistance, a precursor to type 2 diabetes. He and his team have made several important discoveries that may lead to therapeutics that target obesity and insulin resistance.

Research Projects

Inflammation and insulin resistance

Group Leader: Dr Graeme Lancaster

In the past decade 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 (see Figure below). 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. 

The role of  dietary fat and overnutrition in the aetiology of insulin resistance 

Group Leader: Dr Clinton Bruce

Overnutrition leads to excess lipid deposition in tissues such as skeletal muscle and liver. Since these organs are not normally storage depots for fat they become pathogenic during overfeeding. When lipid is stored in these tissues they become “lipotoxic” and eventually insulin resistant. One strategy to overcome lipid storage is to increase the oxidation of the lipid by enhanicing mitochondrial capacity (see Figure below). In this group we study mechanism by which a) certain lipid species dysregulate muscle metabolism and b) we can enhance lipid oxidation. We hope to derive new drug targets that can reduce fat storage and/or increase fat oxidation when people over eat.

The role of pro-inflammatory cytokines in mediating insulin resistance 

Group Leader: Dr Vance Matthews

Many years ago, we discovered that interleukin-6 (IL-6), a plieotropic cytokine produced by many cells/tissues in response to stress, is actually produced by skeletal muscle during contraction. In a series of subsequent studies we were able to show that this and other "IL-6 family" cytokines are a potential therapeutic target to treat obesity via actions on several tissues including the skeletal muscle, the liver and the brain. These projects are on-going as we aim to elucidate the precise molecular mechanism by which these cytokines signal to protect against obesity-induced insulin resistance.

Lab Head Profile

Professor Mark Febbraio
Head, Cellular and Molecular Metabolism Laboratory

Professor Febbraio is a Principal Research Fellow of the NHMRC, is the head of the Cellular and Molecular Metabolism Laboratory and Director of Basic Science in the Division of Metabolism and Obesity at the Baker IDI Heart & Diabetes Research Institute.

He currently oversees approximately 30 staff and students. His laboratory is focussed on understanding cellular and molecular mechanisms associated with lipid-induced inflammation and insulin resistance. 

He has made the vital discovery that muscles produce and secrete cytokines that have biological reactivity. This has lead to the very important discovery that IL-6 and other IL-6 family cytokines can be used as anti-obesogenic compounds and this has culminated in the publications in journals such as Nature Medicine, Journal of Clinical Investigation, Cell Metabolism, Proc Natl Acad Sci USA, Diabetes, Journal of Biological Chemistry and FASEB Journal. His work is consistently cited and despite the fact that he published his first paper in 1993 and is only 13 years post-PhD he has an H-index of 39 (39 papers with greater than 39 citations).

Professor Febbraio is regularly invited to overseas scientific symposia including Keystone Symposia and The American Diabetes Association Annual Scientific Meeting.  In March 2008 he gave the Plenary Lecture at The International Diabetes Federation Congress in Wellington NZ. He has been asked to examine several Ph. D theses within Australia and has been honoured to act as a Thesis Opponent at The Karolinska Institute in Stockholm, Sweden.

Achievements/Awards

Publication Highlights 

• Muscle derived interleukin-6: mechanisms for activation and possible biological roles FASEB J. 16: 1335-1347, 2002. Febbraio MA, Pedersen BK. 
• 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 52: 2338-2345, 2003. Bruce CR, Carey AL, Hawley JA, Febbraio MA.
• Skeletal myocytes are the source of Interleukin-6 mRNA expression and protein release during contraction: evidence of fiber type specificity. FASEB J 18: 992-994, 2004. Hiscock N, Chan MH, Bisucci T, Darby IA, Febbraio MA.
• Interleukin-6 is a novel factor mediating glucose homeostasis in skeletal muscle contraction. Diabetes 53: 1643-1648, 2004. Febbraio MA., Hiscock N, Sacchetti M, Fischer CP, Pedersen BK.
• Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins J Biol Chem. 280: 23349-23355, 2005. Lancaster GI, Febbraio MA.

Key Staff

Contact

Direct +61 3 8532 1767
Mobile +61 402 363 194
Email: mark.febbraio@bakeridi.edu.au

Related Links

Diabetes Treatment May Lie In Helping Muscles To Burn Fat Better news article in Medical News Today

Solution to insulin puzzle on track - article in ABC Science