Prof Michael Cowley - Researcher Profile

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Address

Department of Physiology
Faculty of Medicine, Nursing & Health Sciences, Clayton

Biography

Leptin may be key to controlling obesity

Obesity is arguably our most significant health epidemic. Almost two thirds of Australians are overweight or obese, and its associated diseases are a major concern for researchers. Professor Michael Cowley is the Director of the Monash Obesity and Diabetes Institute (MODI), which focuses on developing new therapies for obesity and diabetes. Michael is particularly interested in why leptin resistance is high in obese people. He’s also looking at some of our most dangerous obesity-related diseases. 

 

Leptin is a protein hormone that our fat cells secrete to regulate our appetite, metabolism and body weight. Earlier research has established leptin resistance in obese people, and Michael is now expanding on this finding.

“We have a project trying to understand how obesity causes leptin resistance and inflammation in the brain,” Michael says. “Our early work described how leptin acted and from that, we worked out that the system became resistant and stopped responding. We published a paper with Tony Tiganis [a professor in the Department of Biochemistry and Molecular Biology] recently. We established a new enzyme that disrupts leptin signalling. We’ve shown that if we block this enzyme, we can help restore body weight control.

“That work also described how other signals from the body, for example your stomach and intestines, tell the brain how much food is in your stomach and intestines. That map of the brain helped us develop a couple of therapeutics for the treatment of obesity. These were spun out into a company I started called Orexigen Therapeutics, and we’ve just finished phase three trials,” he says.

Another of Michael’s major projects looks at blood glucose regulation in a completely new way. It has also led to clinical trials of an exciting new therapeutic.

“I’m looking at the role of the melanocortin system in regulating blood glucose levels, either through changing outflow from the brain, changing neural tone from the brain, or changing the secretion of pituitary hormones. I’m the director of a company that has a diabetes therapy in phase two trials. It’s a novel drug for increasing insulin sensitivity in type two diabetics. Type two diabetes is caused by becoming insensitive to insulin, so a drug that increases insulin sensitivity will treat it. Eventually type two diabetics need insulin replacement, and this drug is for before that. It’s an oral drug.”

Michael’s obesity research also applies to two more very different diseases, highlighting its translational benefits.

“We have a project looking at how obesity causes heart disease and [we are] developing a new therapeutic to treat obesity-induced heart disease. We think we’ve discovered why obesity gives you heart disease and we’ve preliminarily shown that we can reverse obesity-induced heart disease risks without reducing weight,” he says.

“We’re also doing some work on what causes poly-cystic ovarian syndrome and how that disease is exacerbated by obesity. It’s a dominant cause of infertility in young women.”

 

Qualifications

PHD
Institution: Monash University
Year awarded: 1999
BSC (HONORS)
Institution: Monash University
Year awarded: 1993
BSC
Institution: University of Melbourne
Year awarded: 1989

Publications

Journal Articles

Kievit, P., Halem, H., Marks, D., Dong, J.Z., Glavas, M., Sinnayah, P., Pranger, L., Cowley, M.A., Grove, K., Culler, M.D., 2013, Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques, Diabetes [P], vol 62, issue 2, American Diabetes Association, USA, pp. 490-497.

Simonds, S.E., Cowley, M.A., 2013, Hypertension in obesity: is leptin the culprit?, Trends in Neurosciences [P], vol 36, issue 2, Elsevier Ltd * Trends Journals, UK, pp. 121-132.

Chen, W., Wilson, J.L., Khaksari, M., Cowley, M.A., Enriori, P.J., 2012, Abdominal fat analyzed by DEXA scan reflects visceral body fat and improves the phenotype description and the assessment of metabolic risk in mice, American Journal of Physiology - Endocrinology and Metabolism [E], vol 303, issue 5, American Physiological Society, USA, pp. E635-E643.

Clarke, S.D., Clarke, I.J., Rao, A., Cowley, M.A., Henry, B., 2012, Sex differences in the metabolic effects of testosterone in sheep, Endocrinology [P], vol 153, issue 1, The Endocrine Society, USA, pp. 123-131.

Sabin, M.A., Magnussen, C.G., Juonala, M., Cowley, M.A., Shield, J.P., 2012, The role of pharmacotherapy in the prevention and treatment of paediatric metabolic syndrome - Implications for long-term health, Pharmacological Research [P], vol 65, issue 4, Academic Press, UK, pp. 397-401.

Spanswick, D.C., Simonds, S.E., Cowley, M.A., 2012, Transmitter time: synaptic plasticity and metabolic memory in the hypothalamus, Cell Metabolism [P], vol 15, issue 3, Cell Press, USA, pp. 275-276.

Loh, K., Fukushima, A., Zhang, X.M., Galic, S., Briggs, D.I., Enriori, P., Simonds, S., Wiede, F., Reichenbach, A., Hauser, C., Sims, N.A., Bence, K.K., Zhang, S., Zhang, Z., Kahn, B., Neel, B., Andrews, Z.B., Cowley, M.A., Tiganis, T., 2011, Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance, Cell Metabolism [P], vol 14, issue 5, Cell Press, USA, pp. 684-699.

Enriori, P., Sinnayah, P., Simonds, S., Garcia Rudaz, M., Cowley, M., 2011, Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance, Journal Of Neuroscience [P], vol 31, issue 34, Society of Neuroscience, USA, pp. 12189-12197.

Roth, C.L., Enriori, P., Gebhardt, U., Hinney, A., Muller, H.L., Hebebrand, J., Reinehr, T., Cowley, M.A., 2010, Changes of peripheral alpha-melanocyte-stimulating hormone in childhood obesity, Metabolism: Clinical and Experimental [P], vol 59, issue 2, WB Saunders & Co., USA, pp. 186-194.

Briggs, D.I., Enriori, P.J., Lemus, M.B., Cowley, M.A., Andrews, Z.B., 2010, Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons, Endocrinology [P], vol 151, issue 10, The Endocrine Society, USA, pp. 4745-4755.

Glavas, M.M., Kirigiti, M.A., Xiao, Q.X., Enriori, P.J., Fisher, S.K., Evans, A.E., Grayson, B.E., Cowley, M.A., Smith, M.S., Grove, K.L., 2010, Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet, Endocrinology [P], vol 151, issue 4, The Endocrine Society, USA, pp. 1598-1610.

Horvath, T.L., Sarman, B., Garcia-Caceres, C., Enriori, P., Sotonyi, P., Shanabrough, M., Borok, E., Argente, J., Chowen, J.A., Perez-Tilve, D., Pfluger, P.T., Bronneke, H.S., Levin, B.E., Diano, S., Cowley, M.A., Tschop, M.H., 2010, Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity, Proceedings Of The National Academy Of Sciences O..., vol 107, issue 33, National Academy of Sciences, USA, pp. 14875-14880.

Greenway, F.L., Dunayevich, E., Tollefson, G., Erickson, J., Guttadauria, M., Fujioka, K., Cowley, M.A., 2009, Comparison of combined bupropion and naltrexone therapy for obesity with monotherapy and placebo, Journal of Clinical Endocrinology and Metabolism [P], vol 94, issue 12, The Endocrine Society, USA, pp. 4898-4906.

Greenway, F.L., Whitehouse, M.J., Guttadauria, M., Atkinson, R.L., Fujioka, K., Gadde, K.M., Gupta, A.K., O'Neil, P., Schumacher, D., Smith, D., Dunayevich, E., Tollefson, G., Weber, E., Cowley, M.A., 2009, Rational design of a combination medication for the treatment of obesity, Obesity [P], vol 17, issue 1, Nature Publishing Group, USA, pp. 30-39.

Xu, J., Kirigiti, M.A., Cowley, M.A., Grove, K.L., Smith, M., 2009, Suppression of basal spontaneous gonadotropin-releasing hormone neuronal activity during lactation: Role of inhibitory effects of neuropeptide Y, Endocrinology, vol 150, issue 1, The Endocrine Society, USA, pp. 333-340.

Stefanidis, A., Verty, A., Allen, A.M., Owens, N.C., Cowley, M.A., Oldfield, B.J., 2009, The role of thermogenesis in antipsychotic drug-induced weight gain, Obesity, vol 17, Nature Publishing Group, USA, pp. 16-24.

Hill, J., Williams, K., Ye, C., Luo, J., Balthasar, N., Coppari, R., Cowley, M.A., Cantley, L., Lowell, B., Elmquist, J., 2008, Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice, Journal of Clinical Investigation, vol 118, issue 5, American Society for Clinical Investigation, USA, pp. 1796-1805.

Glavas, M., Grayson, B., Allen, S., Copp, D., Smith, M., Cowley, M.A., Grove, K., 2008, Characterization of brainstem peptide YY (PYY) neurons, The Journal of Comparative Neurology, vol 506, issue 2, John Wiley & Sons Inc, USA, pp. 194-210.

Sinnayah, P., Jobst, E., Rathner, J.A., Caldera-Siu, A.D., Tonelli-Lemos, L., Eusterbrock, A.J., Enriori, P., Pothos, E.N., Grove, K., Cowley, M.A., 2008, Feeding induced by cannabinoids is mediated independently of the melanocortin system, PL o S One (online), vol 3, issue 5, Public Library of Science, United States, pp. 1-12.

Myers, M., Cowley, M.A., Munzberg, H., 2008, Mechanisms of leptin action and leptin resistance, Annual Review of Physiology, vol 70, Annual Reviews, USA, pp. 537-556.

Scarlett, J.M., Zhu, X., Enriori, P., Bowe, D., Batra, A., Levasseur, P.R., Grant, W.F., Meguid, M.M., Cowley, M.A., Marks, D., 2008, Regulation of agouti-related protein messenger ribonucleic acid transcription and peptide secretion by acute and chronic inflammation, Endocrinology, vol 149, issue 10, The Endocrine Society, USA, pp. 4837-4845.

Wu, Q., Howell, M., Cowley, M.A., Palmiter, R., 2008, Starvation after AgRP neuron ablation is independent of melanocortin signaling, Proceedings of the National Academy of Sciences, vol 105, issue 7, National Academy of Sciences, USA, pp. 2687-2692.

Wallingford, N., Sinnayah, P., Bymaster, F.P., Gadde, K., Krishnan, R., McKinney, A., Landbloom, R., Tollefson, G., Cowley, M.A., 2008, Zonisamide Prevents Olanzapine-Associated Hyperphagia, Weight Gain, and Elevated Blood Glucose in Rats, Neuropsychopharmacology, vol 33, Nature Publishing Group, UK & USA, pp. 2922-2933.

Munzberg, H., Jobst, E., Bates, S., Jones, J., Villanueva, E., Leshan, R., Bjornholm, M., Elmquist, J., Sleeman, M., Cowley, M.A., Myers Jr., M., 2007, Appropriate inhibition of orexigenic hypothalamic arcuate nucleus neurons independently of leptin receptor/STAT3 signaling, Journal of Neuroscience, vol 27, issue 1, Society for Neuroscience, USA, pp. 69-74.

Melnick, I., Pronchuk, N., Cowley, M.A., Grove, K., Colmers, W., 2007, Developmental switch in neuropeptide Y and melanocortin effects in the paraventricular nucleus of the hypothalamus, Neuron, vol 56, issue 6, Cell Press, USA, pp. 1103-1115.

Enriori, P., Evans, A., Sinnayah, P., Jobst, E., Tonelli-Lemos, L., Billes, S., Glavas, M., Grayson, B., Perello, M., Nillni, E., Grove, K., Cowley, M.A., 2007, Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons, Cell Metabolism, vol 5, issue 3, Cell Press, USA, pp. 181-194.

Xiao, X., Williams, S., Grayson, B., Glavas, M., Cowley, M.A., Smith, M., Grove, K., 2007, Excess weight gain during the early postnatal period is associated with permanent reprogramming of brown adipose tissue adaptive thermogenesis, Endocrinology, vol 148, issue 9, The Endocrine Society, USA, pp. 4150-4159.

Tang-Christensen, M., Cowley, M.A., 2007, GLP-1 analogs: satiety without malaise?, American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, vol 293, issue 3, American Physiological Society, USA, pp. R981-R982.

Parton, L., Ye, C., Coppari, R., Enriori, P., Choi, B., Zhang, C., Xu, C., Vianna, C., Balthasar, N., Lee, C., Elmquist, J., Cowley, M.A., Lowell, B., 2007, Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity, Nature, vol 449, issue 7159, Nature Publishing Group, UK, pp. 228-232.

Billes, S., Cowley, M.A., 2007, Inhibition of dopamine and norepinephrine reuptake produces additive effects on energy balance in lean and obese mice, Neuropsychopharmacology, vol 32, issue 4, Nature Publishing Group, UK & USA, pp. 822-834.

Konner, A., Janoschek, R., Plum, L., Jordan, S., Rother, E., Ma, X., Xu, C., Enriori, P., Hampel, B., Barsh, G., Kahn, C., Cowley, M.A., Ashcroft, F., Bruning, J., 2007, Insulin action in agrp-expressing neurons is required for suppression of hepatic glucose production, Cell Metabolism, vol 5, issue 6, Cell Press, USA, pp. 438-449.

Scarlett, J., Jobst, E., Enriori, P., Bowe, D., Batra, A., Grant, W., Cowley, M.A., Marks, D., 2007, Regulation of central melanocortin signaling by interleukin-1beta, Endocrinology, vol 148, issue 9, The Endocrine Society, USA, pp. 4217-4225.

Greenway, F., Martin, C., Gupta, A., Cruickshank, S., Whitehouse, J., DeYoung, L., Kamdar, K., Caruso, M., Roberts, A., England, M., Dumas, K., Floy Laidlaw, B., Rogers, B., Cowley, M.A., 2007, Using intranasal lidocaine to reduce food intake, International Journal of Obesity, vol 31, issue 5, Nature Publishing Group, UK, pp. 858-863.

Jobst, E., Enriori, P., Sinnayah, P., Cowley, M.A., 2006, Hypothalamic regulatory pathways and potential obesity treatment targets, Endocrine, vol 29, issue 1, Humana Press Inc, USA, pp. 33-48.

Dhillon, H., Zigman, J., Ye, C., Lee, C., McGovern, R., Tang, V., Kenny, C., White, R., Edelstein, E., Coppari, R., Balthasar, N., Cowley, M.A., Chua Jr., S., Elmquist, J., Lowell, B., 2006, Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis, Neuron, vol 49, issue 2, Cell Press, USA, pp. 191-203.

Reinehr, T., Enriori, P., Harz, K., Cowley, M.A., Roth, C., 2006, Pancreatic polypeptide in obese children before and after weight loss, International Journal of Obesity, vol 30, issue 10, Nature Publishing Group, UK, pp. 1476-1481.

Guo, Y., Ma, L., Enriori, P., Koska, J., Franks, P., Brookshire, T., Cowley, M.A., Salbe, A.D., DelParigi, A., Tataranni, P.A., 2006, Physiological evidence for the involvement of peptide YY in the regulation of energy homeostasis in humans, Obesity, vol 14, issue 9, Nature Publishing Group, USA, pp. 1562-1570.

Heisler, L., Jobst, E., Sutton, G., Zhou, L., Borok, E., Thornton-Jones, Z., Liu, H., Zigman, J., Balthasar, N., Kishi, T., Lee, C., Aschkenasi, C., Zhang, C., Yu, J., Boss, O., Mountjoy, K.G., Clifton, P., Lowell, B., Friedman, J., Horvath, T., Butler, A., Elmquist, J., Cowley, M.A., 2006, Serotonin reciprocally regulates melanocortin neurons to modulate food intake, Neuron, vol 51, issue 2, Cell Press, USA, pp. 239-249.

Enriori, P., Evans, A., Sinnayah, P., Cowley, M.A., 2006, The role of leptin in leptin resistance and obesity, Obesity, vol 88, issue Suppl. 5, Nature Publishing Group, USA, pp. 249-256.

Cowley, M.A., Grove, K., 2006, To be or NUCB2, is nesfatin the answer?, Cell Metabolism, vol 4, issue 6, Cell Press, USA, pp. 421-422.

Grove, K., Cowley, M.A., 2005, Is ghrelin a signal for the development of metabolic systems?, Journal of Clinical Investigation, vol 115, issue 12, American Society for Clinical Investigation, USA, pp. 3393-3397.

Roth, C., Enriori, P., Harz, K., Woelfle, J., Cowley, M.A., Reinehr, T., 2005, Peptide YY is a regulator of energy homeostasis in obese children before and after weight loss, Journal of Clinical Endocrinology and Metabolism, vol 90, issue 12, The Endocrine Society, USA, pp. 6386-6391.

Koegler, F., Enriori, P., Billes, S., Takahashi, D., Martin, M., Clark, R., Evans, A., Grove, K., Cameron, J., Cowley, M.A., 2005, Peptide YY(3-36) inhibits morning, but not evening, food intake and decreases body weight in rhesus macaques, Diabetes, vol 54, issue 11, American Diabetes Association, USA, pp. 3198-3204.

Zhou, L., Williams, T., Lachey, J., Kishi, T., Cowley, M.A., Heisler, L., 2005, Serotonergic pathways converge upon central melanocortin systems to regulate energy balance, Peptides, vol 26, issue 10, Elsevier Inc, USA, pp. 1728-1732.

Batterham, R., Cowley, M.A., Small, C., Herzog, H., Cohen, M., Dakin, C., Wren, A., Brynes, A., Low, M., 2004, BRIEF COMMUNICATION ARISING: Gut hormone PYY3-36 physiologically inhibits food intake, Nature, vol 430, issue 6996, Nature Publishing Group, UK, pp. 3-4.

Cowley, M.A., Grove, K., 2004, Ghrelin-Satisfying a hunger for the mechanism, Endocrinology, vol 145, issue 6, The Endocrine Society, USA, pp. 2604-2606.

Jobst, E., Enriori, P., Cowley, M.A., 2004, The electrophysiology of feeding circuits, Trends in Endocrinology and Metabolism, vol 15, issue 10, Elsevier Ltd, UK, pp. 488-499.

Heisler, L., Cowley, M.A., Kishi, T., Tecott, L.H., Fan, W., Low, M., Smart, J., Rubenstein, M., Tatro, J., Zigman, J., Cone, R., Elmquist, J., 2003, Central serotonin and melanocortin pathways regulating energy homeostasis, Annals of the New York Academy of Sciences, vol 994, Wiley-Blackwell Publishing Inc, USA, pp. 169-174.

Horvath, T., Diano, S., Leranth, C., Garcia-Segura, L., Cowley, M.A., Shananbrough, M., Elsworth, J., Sotonyi, P., Roth, R., Dietrich, E., Matthews, R., Barnstable, C., Redmond Jr., D., 2003, Coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss in a primate model of Parkinson's disease, Endocrinology, vol 144, issue 7, The Endocrine Society, USA, pp. 2757-2760.

Cowley, M.A., Cone, R., Enriori, P., Louiselle, I., Williams, S., Evans, A., 2003, Electrophysiological actions of peripheral hormones on melanocortin neurons, Annals of the New York Academy of Sciences, vol 994, Wiley-Blackwell Publishing Inc, USA, pp. 175-186.

Cowley, M.A., 2003, Hypothalamic melanocortin neurons integrate signals of energy state, European Journal of Pharmacology, vol 480, issue 1-3, Elsevier BV, The Netherlands, pp. 3-11.

Cowley, M.A., Smith, R., Diano, S., Tschop, M.H., Pronchuk, N., Grove, K., Strausburger, C., Bidlingmaier, M., Esterman, M., Heiman, M., Garcia-Segura, L., Nillni, E., Mendez, P., Low, M., Sotonyi, P., Friedman, J., Liu, H., Pinto, S., Colmers, W., Cone, R., Horvath, T., 2003, The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis, Neuron, vol 37, issue 4, Cell Press, USA, pp. 649-661.

Batterham, R., Cowley, M.A., Small, C., Herzog, H., Cohen, M., Dakin, C., Wren, A., Brynes, A., Low, M.J., Ghatei, M., Cone, R., Bloom, S., 2002, LETTER: Gut hormone PYY3-36 physiologically inhibits food intake, Nature, vol 418, Nature Publishing Group, UK, pp. 3-4.

Heisler, L., Cowley, M.A., Tecott, L.H., Fan, W., Low, M., Smart, J., Rubinstein, M., Tatro, J., Marcus, J., Holstege, H., Lee, C., Cone, R., Elmquist, J., 2002, REPORT: Activation of central melanocortin pathways by fenfluramine, Science, vol 297, issue 5581, American Association for the Advancement of Science, USA, pp. 609-611.

Campbell, R., Ffrench-Mullen, J., Cowley, M.A., Smith, M., Grove, K., 2001, Hypothalamic circuitry of neuropeptide Y regulation of neuroendocrine function and food intake via the Y5 receptor subtype, Neuroendocrinology, vol 74, issue 7, S Karger AG, Swizterland, pp. 106-119.

Cowley, M.A., Smart, J., Rubinstein, M., Cerdan, M., Diano, S., Horvath, T., Cone, R., Low, M., 2001, LETTER: Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus, Nature, vol 411, issue 6836, Nature Publishing Group, UK, pp. 480-484.

Cone, R., Cowley, M.A., Butler, A., Fan, W., Marks, D., Low, M., 2001, The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis, International Journal of Obesity, vol 25, issue Suppl. 5, Nature Publishing Group, UK, pp. S63-S67.

Grove, K., Campbell, R., Ffrench-Mullen, J., Cowley, M.A., Smith, M., 2000, Neuropeptide Y Y5 receptor protein in the cortical/limbic system and brainstem of the rat: expression on gamma-aminobutyric acid and corticotropin-releasing hormone neurons, Neuroscience, vol 100, issue 4, Pergamon, UK & France, pp. 731-740.

Other

Cowley, M., Weber, E., 2010, Compositions for affecting weight loss, Australia.

Butler, A., Small, C., Low, M., Bloom, S., Ghatei, M., Batterham, R., Cone, R., Cowley, M., 2009, Modification of feeding behavior, Australia.

Butler, A., Cone, R., Cowley, M., Low, M., 2008, Assessment of neurons in the arcuate nucleus to screen for agents that modify feeding behaviior, Australia.

Butler, A., Small, C., Low, M., Bloom, S., Ghatei, M., Batterham, R., Cone, R., Cowley, M., 2008, Modification of feeding behavior, Australia.

Postgraduate Research Supervisions

Current Supervision

Program of Study:
(DOCTORATE BY RESEARCH).
Thesis Title:
Brain control of blood glucose levels.
Supervisors:
Cowley, M (Main), Enriori, P (Associate).
Program of Study:
(DOCTORATE BY RESEARCH).
Thesis Title:
Does obesity related hypertension develop as a consequence of hyperleptinaemia, through leptin's actions in the dorso medial hypothalamus.
Supervisors:
Cowley, M (Main), Enriori, P (Associate).
Program of Study:
(DOCTORATE BY RESEARCH).
Thesis Title:
Examination of metabolic alterations involved in PCOS through the development of a new model.
Supervisors:
Enriori, P (Joint-co), Garcia Rudaz, M (Joint), Cowley, M (Associate).
Program of Study:
(DOCTORATE BY RESEARCH).
Thesis Title:
The role of ChREBP in insulin resistance and hepatic lipid metabolism.
Supervisors:
Cowley, M (Joint), Sleeman, M (Joint-co).