Author
Listed:
- Mirjam Geibel
(University of Oxford
Centre for Neuroregeneration, University of Edinburgh
European Molecular Biology Laboratory, Mouse Biology Unit)
- Sylvia Badurek
(Centre for Neuroregeneration, University of Edinburgh
European Molecular Biology Laboratory, Mouse Biology Unit)
- Jacqueline M. Horn
(University of Oxford
Centre for Neuroregeneration, University of Edinburgh)
- Chinnavuth Vatanashevanopakorn
(University of Oxford
Centre for Neuroregeneration, University of Edinburgh
Faculty of Medicine Siriraj Hospital, Mahidol University)
- Juraj Koudelka
(Centre for Neuroregeneration, University of Edinburgh)
- Claudia M. Wunderlich
(Max Planck Institute for Neurological Research
Center for Molecular Medicine Cologne (CMMC), University of Cologne
Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD))
- Hella S. Brönneke
(Max Planck Institute for Neurological Research
CECAD, Mouse Phenotyping Core Facility, Cologne)
- F. Thomas Wunderlich
(Max Planck Institute for Neurological Research
Center for Molecular Medicine Cologne (CMMC), University of Cologne
Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD))
- Liliana Minichiello
(University of Oxford
Centre for Neuroregeneration, University of Edinburgh
European Molecular Biology Laboratory, Mouse Biology Unit)
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.
Suggested Citation
Mirjam Geibel & Sylvia Badurek & Jacqueline M. Horn & Chinnavuth Vatanashevanopakorn & Juraj Koudelka & Claudia M. Wunderlich & Hella S. Brönneke & F. Thomas Wunderlich & Liliana Minichiello, 2014.
"Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity,"
Nature Communications, Nature, vol. 5(1), pages 1-15, May.
Handle:
RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4427
DOI: 10.1038/ncomms4427
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