Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity

Mirjam Geibel, Sylvia Badurek, Jacqueline M. Horn, Chinnavuth Vatanashevanopakorn, Juraj Koudelka, Claudia M. Wunderlich, Hella S. Brönneke, F. Thomas Wunderlich and Liliana Minichiello ()
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Mirjam Geibel: University of Oxford
Sylvia Badurek: Centre for Neuroregeneration, University of Edinburgh
Jacqueline M. Horn: University of Oxford
Chinnavuth Vatanashevanopakorn: University of Oxford
Juraj Koudelka: Centre for Neuroregeneration, University of Edinburgh
Claudia M. Wunderlich: Max Planck Institute for Neurological Research
Hella S. Brönneke: Max Planck Institute for Neurological Research
F. Thomas Wunderlich: Max Planck Institute for Neurological Research
Liliana Minichiello: University of Oxford

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4427

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