Hypothalamic glycogen synthase kinase 3β has a central role in the regulation of food intake and glucose metabolism

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*

*Corresponding author for this work
42 Citations (Scopus)

Abstract

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 Lep ob/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 intracellularmediator 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.

Original languageEnglish
JournalBiochemical Journal
Volume447
Issue number1
Pages (from-to)175-184
Number of pages10
ISSN0264-6021
DOIs
Publication statusPublished - 01.10.2012

DFG Research Classification Scheme

  • 205-17 Endocrinology, Diabetology, Metabolism

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