Mark Cleasby
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Mark is a Research Fellow in the Cardiovascular Group of the Lifestyle research programme. His research interests lie in Endocrinology and Metabolism and specifically in the pathogenesis of insulin resistance in tissues.
Biography
Mark graduated as a Bachelor of Veterinary Medicine and Surgery in 1994 from the University of Edinburgh. Following this he worked as a small animal general veterinary practitioner at various practices until 1998. During this period Mark developed a particular interest in Internal medicine and Endocrinology. In 1998 Mark returned to the University of Edinburgh to undertake a PhD in the Endocrinology Unit of the Department of Medical Sciences, supervised by Professors Jonathan R. Seckl and Brian R Walker. His PhD thesis, entitled "Mechanisms of insulin resistance in prenatally programmed rats", was awarded in 2002.
From 2002 to 2007 Mark worked as Research Officer and subsequently Senior Research Officer in the Diabetes and Obesity Program of the Garvan Institute, Sydney, Australia. During this period he investigated the molecular and physiological basis of lipid- induced insulin resistance in vivo under the supervision of Professors Edward W. Kraegen and David E. James, and Associate Professor Gregory J. Cooney.
Mark joined the Royal Veterinary College in March 2007 to establish a research group investigating the molecular and physiological basis of insulin resistance and diabetes.
Research
In Mark's work to date he has investigated the roles of environmental, genetic and prenatal factors in the development of insulin resistance, predominantly using an in vivo integrative physiology approach. In particular Mark has adapted the technique of in vivo electrotransfer for use in the acute interrogation of candidate insulin resistance genes in skeletal muscle, the tissue which is largely responsible for determining whole body insulin sensitivity.
Mark's principal programme of research at the RVC concerns the mechanisms whereby adiponectin influences insulin sensitivity in muscle and liver. Adiponectin is a molecule secreted in large quantities by adipose tissue which has been shown to cause increases in fatty acid oxidation and glucose disposal into muscle; effects thought to be mediated in part by activation of the cellular energy status-sensing molecule AMP-activated protein kinase (AMPK).
Whereas inverse correlations have now been widely recorded between the levels of circulating adiponectin and the degree of whole body adiposity or insulin resistance, it is less clear whether and how adiponectin achieves a direct effect upon insulin target tissues to have these effects. Mark is investigating the roles of putative adiponectin signalling and downstream target molecules in the determination of the effects of adiponectin in muscle and liver and their significance for tissue insulin sensitivity. This work has the potential to identify key players in the development of insulin resistance and the metabolic syndrome and thus inform development of novel therapeutics both in human and other species.
Mark's work is currently funded by a Wellcome Trust University Award, a National Health and Medical Research Council of Australia Project Grant and a Royal Society Research Grant.
Mark is currently collaborating with Professor Edward W. Kraegen, Garvan Institute of Medical Research; Dr Jonathan P. Whitehead, University of Queensland; Associate Professor Aimin Xu, University of Hong Kong and Dr Pauline Jamieson, University of Edinburgh.
Research group members:
1) Sejal Patel, BSc PhD, Research assistant (from June 2009).
2) Nicola Talbot, BSc MSc, Postgraduate student (from October 2009).
Selected Publications
RAMAKRISHNAN S. N., LAU P., CROWTHER L. M., CLEASBY M. E., MILLARD S., LEONG G. M., COONEY G. J. & MUSCAT G. E. (2009) Rev-erb beta regulates the Srebp-1c promoter and mRNA expression in skeletal muscle cells. Biochem Biophys Res Commun. 388, 654-9. PubMed ID 19682428
POLKINGHORNE, E., LAU, Q., COONEY, G. J., KRAEGEN, E. W. & CLEASBY, M. E. (2008) Local activation of the IkappaK-NF-kappaB pathway in muscle does not cause insulin resistance. Am J Physiol Endocrinol Metab 294, E316-325. PubMed ID 18029440
CLEASBY, M. E., REINTEN, T. A., COONEY, G. J., JAMES, D. E. & KRAEGEN, E. W. (2007) Functional studies of Akt isoform specificity in skeletal muscle in vivo; maintained insulin sensitivity despite reduced insulin receptor substrate-1 expression. Mol Endocrinol 21, 215-228. PubMed ID 17021050
BRUCE, C. R., BROLIN, C., TURNER, N., CLEASBY, M. E., VAN DER LEIJ, F. R., COONEY, G. J. & KRAEGEN, E. W. (2007) Overexpression of carnitine palmitoyltransferase I in skeletal muscle in vivo increases fatty acid oxidation and reduces triacylglycerol esterification. Am J Physiol Endocrinol Metab 292, E1231-1237. PubMed ID 17179390
MAXWELL, M. A., CLEASBY, M. E., HARDING, A., STARK, A., COONEY, G. J. & MUSCAT, G. E. (2005) Nur77 regulates lipolysis in skeletal muscle cells. Evidence for cross-talk between the beta-adrenergic and an orphan nuclear hormone receptor pathway. J Biol Chem 280, 12573-12584. PubMed ID 15640143
CLEASBY, M. E., DAVEY, J. R., REINTEN, T. A., GRAHAM, M. W., JAMES, D. E., KRAEGEN, E. W. & COONEY, G. J. (2005) Acute bidirectional manipulation of muscle glucose uptake by in vivo electrotransfer of constructs targeting glucose transporter genes. Diabetes 54, 2702-2711. PubMed ID 16123360
YE, J. M., DZAMKO, N., CLEASBY, M. E., HEGARTY, B. D., FURLER, S. M., COONEY, G. J. & KRAEGEN, E. W. (2004) Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin. Diabetologia 47, 1306-1313. PubMed ID 15232684
CLEASBY, M. E., DZAMKO, N., HEGARTY, B. D., COONEY, G. J., KRAEGEN, E. W. & YE, J. M. (2004) Metformin prevents the development of acute lipid-induced insulin resistance in the rat through altered hepatic signaling mechanisms. Diabetes 53, 3258-3266. PubMed ID 15561958
CLEASBY, M. E., LIVINGSTONE, D. E., NYIRENDA, M. J., SECKL, J. R. & WALKER, B. R. (2003) Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood? Eur J Endocrinol 148, 129-138. PubMed ID 12534366
CLEASBY, M. E., KELLY, P. A., WALKER, B. R. & SECKL, J. R. (2003) Programming of rat muscle and fat metabolism by in utero overexposure to glucocorticoids. Endocrinology 144, 999-1007. PubMed ID 12586777
SECKL, J. R., CLEASBY, M. & NYIRENDA, M. J. (2000) Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming. Kidney Int 57, 1412-1417. PubMed ID 10760076