GSK3β (glycogen synthase kinase 3β) is a ubiquitous kinase that plays a key role in multiple intracellular signalling pathways, and increased GSK3β activity is implicated in disorders ranging from cancer to Alzheimer's disease. In the present study, we provide the first evidence of increased hypothalamic signalling via GSK3β in leptin-deficient Lepob/ob mice and show that intracerebroventricular injection of a GSK3β inhibitor acutely improves glucose tolerance in these mice. The beneficial effect of the GSK3β inhibitor was dependent on hypothalamic signalling via PI3K (phosphoinositide 3-kinase), a key intracellular mediator of both leptin and insulin action. Conversely, neuron-specific overexpression of GSK3β in the mediobasal hypothalamus exacerbated the hyperphagia, obesity and impairment of glucose tolerance induced by a high-fat diet, while having little effect in controls fed standard chow. These results demonstrate that increased hypothalamic GSK3β signalling contributes to deleterious effects of leptin deficiency and exacerbates high-fat diet-induced weight gain and glucose intolerance.
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October 2012
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September 12 2012
Hypothalamic glycogen synthase kinase 3β has a central role in the regulation of food intake and glucose metabolism
Jonas Benzler;
Jonas Benzler
1
*Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
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Goutham K. Ganjam;
Goutham K. Ganjam
1
*Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
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Manon Krüger;
Manon Krüger
*Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
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Olaf Pinkenburg;
Olaf Pinkenburg
†Department of Immunology, Faculty of Medicine, Philipps University Marburg, Marburg, Germany
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Maria Kutschke;
Maria Kutschke
‡Institute for Diabetes and Obesity, Helmholtz Centre, Munich, Germany
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Sigrid Stöhr;
Sigrid Stöhr
*Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
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Juliane Steger;
Juliane Steger
*Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
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Christiane E. Koch;
Christiane E. Koch
*Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
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Rebecca Ölkrug;
Rebecca Ölkrug
*Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
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Michael W. Schwartz;
Michael W. Schwartz
§Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, WA, U.S.A.
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Peter R. Shepherd;
Peter R. Shepherd
∥Maurice Wilkins Centre for Molecular Biodiscovery and Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
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David R. Grattan;
David R. Grattan
¶Centre for Neuroendocrinology and Department of Anatomy and Structural Biology, University of Otago, Dunedin, New Zealand
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Alexander Tups
Alexander Tups
2
*Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
2To whom correspondence should be addressed (email alexander.tups@staff.uni-marburg.de).
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Publisher: Portland Press Ltd
Received:
May 22 2012
Revision Received:
July 26 2012
Accepted:
August 01 2012
Accepted Manuscript online:
August 01 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 447 (1): 175–184.
Article history
Received:
May 22 2012
Revision Received:
July 26 2012
Accepted:
August 01 2012
Accepted Manuscript online:
August 01 2012
Citation
Jonas Benzler, Goutham K. Ganjam, Manon Krüger, Olaf Pinkenburg, Maria Kutschke, Sigrid Stöhr, Juliane Steger, Christiane E. Koch, Rebecca Ölkrug, Michael W. Schwartz, Peter R. Shepherd, David R. Grattan, Alexander Tups; Hypothalamic glycogen synthase kinase 3β has a central role in the regulation of food intake and glucose metabolism. Biochem J 1 October 2012; 447 (1): 175–184. doi: https://doi.org/10.1042/BJ20120834
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