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Title: Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity
Authors: Mirjam Geibel
Sylvia Badurek
Jacqueline M. Horn
Chinnavuth Vatanashevanopakorn
Juraj Koudelka
Claudia M. Wunderlich
Hella S. Brönneke
F. Thomas Wunderlich
Liliana Minichiello
University of Oxford
University of Edinburgh
European Molecular Biology Laboratory
Mahidol University
Max Planck Institute for Metabolism Research
University of Cologne
Cologne Excellence Cluster for Cellular Stress Responses in Aging Associated Diseases (CECAD)
Keywords: Biochemistry, Genetics and Molecular Biology;Chemistry;Physics and Astronomy
Issue Date: 12-Mar-2014
Citation: Nature Communications. Vol.5, (2014)
Abstract: Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity leads to debilitating neuroendocrine or metabolic disorders such as Cushing's syndrome (CS). Glucocorticoids control HPA axis activity through negative feedback to the pituitary gland and the central nervous system (CNS). However, the cellular mechanisms involved are poorly understood, particularly in the CNS. Here we show that, in mice, selective loss of TrkB signalling in cholecystokinin (CCK)-GABAergic neurons induces glucocorticoid resistance, resulting in increased corticotrophin-releasing hormone expression, chronic hypercortisolism, adrenocortical hyperplasia, glucose intolerance and mature-onset obesity, reminiscent of the human CS phenotype. Interestingly, obesity is not due to hyperphagia or decreased energy expenditure, but is associated with increased de novo lipogenesis in the liver. Our study therefore identifies CCK neurons as a novel and critical cellular component of the HPA axis, and demonstrates the requirement of TrkB for the transmission of glucocorticoid signalling. © 2014 Macmillan Publishers Limited.
ISSN: 20411723
Appears in Collections:Scopus 2011-2015

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