Mark A. Febbraio
Garvan Institute of Medical Research
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Featured researches published by Mark A. Febbraio.
Nature Reviews Endocrinology | 2012
Bente Klarlund Pedersen; Mark A. Febbraio
During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.
Diabetes | 2006
Andrew L. Carey; Gregory R. Steinberg; S. Lance Macaulay; Walter G. Thomas; Anna G. Holmes; Georg Ramm; Oja Prelovsek; Cordula Hohnen-Behrens; Matthew J. Watt; David E. James; Bruce E. Kemp; Bente Klarlund Pedersen; Mark A. Febbraio
Although interleukin-6 (IL-6) has been associated with insulin resistance, little is known regarding the effects of IL-6 on insulin sensitivity in humans in vivo. Here, we show that IL-6 infusion increases glucose disposal without affecting the complete suppression of endogenous glucose production during a hyperinsulinemic-euglycemic clamp in healthy humans. Because skeletal muscle accounts for most of the insulin-stimulated glucose disposal in vivo, we examined the mechanism(s) by which IL-6 may affect muscle metabolism using L6 myotubes. IL-6 treatment increased fatty acid oxidation, basal and insulin-stimulated glucose uptake, and translocation of GLUT4 to the plasma membrane. Furthermore, IL-6 rapidly and markedly increased AMP-activated protein kinase (AMPK). To determine whether the activation of AMPK mediated cellular metabolic events, we conducted experiments using L6 myotubes infected with dominant-negative AMPK α-subunit. The effects described above were abrogated in AMPK dominant-negative–infected cells. Our results demonstrate that acute IL-6 treatment enhances insulin-stimulated glucose disposal in humans in vivo, while the effects of IL-6 on glucose and fatty acid metabolism in vitro appear to be mediated by AMPK.
The FASEB Journal | 2003
Rebecca L. Starkie; Sisse R. Ostrowski; Sune Jauffred; Mark A. Febbraio; Bente Klarlund Pedersen
During “nondamaging” exercise, skeletal muscle markedly releases interleukin (IL)‐6, and it has been suggested that one biological role of this phenomenon is to inhibit the production of tumor necrosis factor (TNF)‐α, which is known to cause pathogenesis such as insulin resistance and atherosclerosis. To test this hypothesis, we performed three experiments in which eight healthy males either rested (CON), rode a bicycle for 3 h (EX), or were infused with recombinant human IL‐6 (rhIL‐6) for 3 h while they rested. After 2.5 h, the volunteers received a bolus of Escherichia coli lipopolysaccharide endotoxin (0.06 ng/kg) i.v. to induce low‐grade inflammation. In CON, plasma TNF‐α increased significantly in response to endotoxin. In contrast, during EX, which resulted in elevated IL‐6, and rhIL‐6, the endotoxin‐induced increase in TNF‐α was totally attenuated. In conclusion, physical exercise and rhIL‐6 infusion at physiological concentrations inhibit endotoxin‐induced TNF‐α production in humans. Hence, these data provide the first experimental evidence that physical activity mediates antiinflammatory activity and suggest that the mechanism include IL‐6, which is produced by and released from exercising muscles.
Journal of Clinical Investigation | 2007
Andrea L. Hevener; Jerrold M. Olefsky; Donna Reichart; M. T. Audrey Nguyen; Gautam Bandyopadyhay; Ho-Yin Leung; Matthew J. Watt; Christopher Benner; Mark A. Febbraio; Anh-Khoi Nguyen; Brian Folian; Shankar Subramaniam; Frank J. Gonzalez; Christopher K. Glass; Mercedes Ricote
PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.
Journal of Biological Chemistry | 2005
Graeme I. Lancaster; Mark A. Febbraio
The heat shock proteins (HSPs) are a family of intracellular proteins found in all eukaryotes and prokaryotes. Their functions are well characterized and are central to maintaining cellular homeostasis and in promoting cell survival in response to stressful cellular conditions. However, several studies provide evidence that specific members of the HSP family might be secreted via an unidentified exocytotic pathway. Here we show that exosomes, small membrane vesicles that are secreted by numerous cell types, contribute to the release of HSP70 from human peripheral blood mononuclear cells (PBMCs) in both basal and stress-induced (heat shock at 40 or 43 °C for 1 h) states. HSP70 release from PBMCs is independent of the common secretory pathway because Brefeldin A, an inhibitor of the classical protein transport pathway, did not block HSP70 release. Furthermore, we show that HSP70 release from PBMCs does not occur via a lipid raft-dependent pathway, because treatment with methyl-β-cyclodextrin, a raft-disrupting drug, had no affect on HSP70 release. To examine whether exosomes contributed to HSP70 release from PBMCs, exosomes were purified from PBMC cultures, and exosomal number and HSP70 content were determined. We demonstrate that although heat shock does not influence the exosomal secretory rate, the HSP70 content of exosomes isolated from heat shocked PBMCs is significantly higher than control. These data identify a novel secretory pathway by which HSP70 can be actively released from cells in both the basal and stress-induced state.
Cell Metabolism | 2009
Kim Loh; Haiyang Deng; Atsushi Fukushima; Xiaochu Cai; Benoit Boivin; Sandra Galic; Clinton R. Bruce; Benjamin James Shields; Beata Skiba; Lisa M Ooms; Nigel K. Stepto; Ben Jing Wu; Christina A. Mitchell; Nicholas K. Tonks; Matthew J. Watt; Mark A. Febbraio; Peter J. Crack; Sofianos Andrikopoulos; Tony Tiganis
Chronic reactive oxygen species (ROS) production by mitochondria may contribute to the development of insulin resistance, a primary feature of type 2 diabetes. In recent years it has become apparent that ROS generation in response to physiological stimuli such as insulin may also facilitate signaling by reversibly oxidizing and inhibiting protein tyrosine phosphatases (PTPs). Here we report that mice lacking one of the key enzymes involved in the elimination of physiological ROS, glutathione peroxidase 1 (Gpx1), were protected from high-fat-diet-induced insulin resistance. The increased insulin sensitivity in Gpx1(-/-) mice was attributed to insulin-induced phosphatidylinositol-3-kinase/Akt signaling and glucose uptake in muscle and could be reversed by the antioxidant N-acetylcysteine. Increased insulin signaling correlated with enhanced oxidation of the PTP family member PTEN, which terminates signals generated by phosphatidylinositol-3-kinase. These studies provide causal evidence for the enhancement of insulin signaling by ROS in vivo.
Proceedings of the National Academy of Sciences of the United States of America | 2008
Jason Chung; Anh Nguyen; Darren C. Henstridge; Anna G. Holmes; M. H. Stanley Chan; Jose L. Mesa; Graeme I. Lancaster; Robert J. Southgate; Clinton R. Bruce; S. Duffy; Ibolya Horváth; Ruben Mestril; Matthew J. Watt; Philip L. Hooper; Bronwyn A. Kingwell; László Vígh; Andrea L. Hevener; Mark A. Febbraio
Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of κB kinase, and tumor necrosis factor-α, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.
Exercise and Sport Sciences Reviews | 2005
Mark A. Febbraio; Bente Klarlund Pedersen
The concentration of plasma interleukin-6 (IL-6) increases during physical exercise, but until recently the cellular origin of this increase has been unknown. Recent work has identified that skeletal muscle is a major source of this increase and the release of IL-6 from muscle can mediate metabolic processes. IL-6 is, therefore, the first identified “myokine” released from muscle that can now be termed an endocrine organ.
Diabetologia | 2009
Vance B. Matthews; Mb Åström; Mhs Chan; Clinton R. Bruce; K. S. Krabbe; Oja Prelovsek; Thorbjorn Akerstrom; Christina Yfanti; Christa Broholm; Ole Hartvig Mortensen; Milena Penkowa; Pernille Hojman; Alaa Zankari; Matthew J. Watt; Helle Bruunsgaard; Bente Klarlund Pedersen; Mark A. Febbraio
It has been brought to our attention following an investigation into the work of Bente Klarlund Pedersen by the Danish Committees for Scientific Dishonesty, that the erratum published in 2012 was insufficient to correct this article. Although the data published in the Diabetologia paper were previously unpublished, the data from the biological material collected from the additional eight healthy men presented in Fig. 1b and c originated from a previous study that was not referenced [1]. In addition, while these eight healthy subjects performed the same type of exercise at the same intensity, the duration was different. The following description of the methodology and Fig. 1 legend correct these oversights. The authors would like to reiterate that these methodological oversights in no way affect either the data presented in the paper or the conclusions reached. The authors also apologise to both the journal and its readership for these oversights.
Nature Immunology | 2014
J Mauer; B Chaurasia; J Goldau; Mc Vogt; J Ruud; Khoa D. Nguyen; Sebastian Theurich; Ac Hausen; J Schmitz; Hella S. Brönneke; Emma Estevez; Tamara L. Allen; Andrea Mesaros; Linda Partridge; Mark A. Febbraio; Ajay Chawla; Ft Wunderlich; Jens C. Brüning
Obesity and insulin resistance are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation, however its role in this context remains controversial. Here, we show that mice with inactivated Il6ra gene in myeloid cells (Il6raΔmyel) displayed exaggerated deterioration of glucose homeostasis upon diet-induced obesity due to enhanced insulin resistance. Insulin target tissues showed increased inflammation and a shift in macrophage polarization. IL-6 induced IL-4-receptor expression and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6raΔmyel mice were resistant to IL-4-mediated alternative macrophage polarization and exhibited increased susceptibility to LPS-induced endotoxemia. These results reveal IL-6 signaling as an important determinant for alternative macrophage-activation and assign IL-6 an unexpected homeostatic role to limit inflammation.Obesity and resistance to insulin are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation; however, its role in this context remains controversial. Here we found that mice with an inactivated gene encoding the IL-6Rα chain of the receptor for IL-6 in myeloid cells (Il6raΔmyel mice) developed exaggerated deterioration of glucose homeostasis during diet-induced obesity, due to enhanced resistance to insulin. Tissues targeted by insulin showed increased inflammation and a shift in macrophage polarization. IL-6 induced expression of the receptor for IL-4 and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6raΔmyel mice were resistant to IL-4-mediated alternative polarization of macrophages and exhibited enhanced susceptibility to lipopolysaccharide (LPS)-induced endotoxemia. Our results identify signaling via IL-6 as an important determinant of the alternative activation of macrophages and assign an unexpected homeostatic role to IL-6 in limiting inflammation.