title: Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity.
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.
authors.affiliation: 1] Department of Pharmacology, University of Oxford, OX1 3QT Oxford, UK [2] Centre for Neuroregeneration, University of Edinburgh, EH16 4SB Edinburgh, UK [3] European Molecular Biology Laboratory, Mouse Biology Unit, 00015 Monterotondo, Italy.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Geibel
authors.affiliation: 1] Centre for Neuroregeneration, University of Edinburgh, EH16 4SB Edinburgh, UK [2] European Molecular Biology Laboratory, Mouse Biology Unit, 00015 Monterotondo, Italy.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Badurek
authors.affiliation: 1] Department of Pharmacology, University of Oxford, OX1 3QT Oxford, UK [2] Centre for Neuroregeneration, University of Edinburgh, EH16 4SB Edinburgh, UK.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Horn
authors.affiliation: 1] Department of Pharmacology, University of Oxford, OX1 3QT Oxford, UK [2] Centre for Neuroregeneration, University of Edinburgh, EH16 4SB Edinburgh, UK [3] Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Chinnavuth
authors.initials: C
authors.lastname: Vatanashevanopakorn
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, EH16 4SB Edinburgh, UK.
authors.forename: Juraj
authors.initials: J
authors.lastname: Koudelka
authors.affiliation: 1] Max Planck Institute for Neurological Research, Cologne, 50931 Cologne, Germany [2] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany [3] Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD), 50674 Cologne, Germany.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Wunderlich
authors.affiliation: 1] Max Planck Institute for Neurological Research, Cologne, 50931 Cologne, Germany [2] CECAD, Mouse Phenotyping Core Facility, Cologne, 50674 Cologne, Germany.
authors.forename: Hella S
authors.initials: HS
authors.lastname: Brönneke
authors.affiliation: 1] Max Planck Institute for Neurological Research, Cologne, 50931 Cologne, Germany [2] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany [3] Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD), 50674 Cologne, Germany.
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.affiliation: 1] Department of Pharmacology, University of Oxford, OX1 3QT Oxford, UK [2] Centre for Neuroregeneration, University of Edinburgh, EH16 4SB Edinburgh, UK [3] European Molecular Biology Laboratory, Mouse Biology Unit, 00015 Monterotondo, Italy.
authors.forename: Liliana
authors.initials: L
authors.lastname: Minichiello
mesh_terms: D000818:Animals; D001823:Body Composition / Q000187:drug effects; D002153:Calorimetry, Indirect; D002766:Cholecystokinin / Q000235:genetics / Q000378:metabolism*; D003480:Cushing Syndrome / Q000235:genetics / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D015151:Immunoblotting; D017403:In Situ Hybridization; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB
chemical_list: D002766:Cholecystokinin; D008562:Membrane Glycoproteins; D015735:Mifepristone; D011505:Protein-Tyrosine Kinases; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB