cholecystokinin and Cushing-Syndrome

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.

Topics: Animals; Body Composition; Calorimetry, Indirect; Cholecystokinin; Cushing Syndrome; Eating; Female; GABAergic Neurons; Immunoblotting; In Situ Hybridization; Male; Membrane Glycoproteins; Mice; Mifepristone; Obesity; Protein-Tyrosine Kinases

Examination of the exocrine function of the pancreas, carried out with secretin-pancreozymin test in patients with adrenal diseases, has shown two errors, that may be easily corrected, usually made in such examinations. One of these errors is neglected analysis of the basal secretion, that may be informative in a number of cases; the other, resultant from the first one, is comparison of the stimulated secretion with but one basal period sample, that eventually leads to inaccurate results. An adequate picture of the exocrine pancreatic secretion may be obtained if the methods of investigation are changed, i.e. the duration of the basal phase be prolonged to 1 hour.

Topics: Adrenal Insufficiency; Amylases; Cholecystokinin; Clinical Enzyme Tests; Cushing Syndrome; Humans; Pancreas; Pancreatic Function Tests; Time Factors; Trypsin

Radioimmunoassay (RIA) was used to measure the response of serum trypsin to intravenous secretin and pancreozymin in 16 subjects with adrenocortical hyperfunction (group I) versus 6 subjects with hypercorticism (group II). In group I the enzyme reaction to the peptides was active and long-term. A similar rise in trypsin level occurred equally in patients free of chronic pancreatitis often present in Itsenko++ -Cushing syndrome. In group II patients RIA trypsin values comply with normal levels. The data obtained suggest an affected pancreatic status in adrenal hyperfunction both in the presence and absence of chronic pancreatitis which minimizes the informative value of the test in identification of chronic pancreatitis in endogenic hypercorticism.

Topics: Adult; Cholecystokinin; Cushing Syndrome; Female; Humans; Male; Middle Aged; Radioimmunoassay; Secretin; Stimulation, Chemical; Trypsin

We found small amounts of cholecystokinin in the normal human adenohypophysis and therefore examined pituitary tumors from 87 patients with acromegaly, Cushing's disease, Nelson's syndrome, prolactinoma, or inactive pituitary adenomas. Five adenomas associated with Nelson's syndrome contained increased amounts of cholecystokinin, the concentrations being extremely high in two: 8281 and 13,453 pmol per gram as compared with less than 30 pmol per gram in normal pituitary glands. The cholecystokinin concentrations were moderately increased in adenomas from another 12 patients, of whom 5 had Cushing's disease and 7 acromegaly with adenomas containing ACTH. The cholecystokinin peptides from the tumors were smaller and less sulfated than cholecystokinin from normal pituitary glands. We conclude that ACTH-producing pituitary cells may also produce an altered form of cholecystokinin.

Topics: Acromegaly; Adenoma; Adrenocorticotropic Hormone; Cholecystokinin; Cushing Syndrome; Hormones, Ectopic; Humans; Nelson Syndrome; Pituitary Gland, Anterior; Pituitary Neoplasms; Prolactin