title: Impaired glucocorticoid production and response to stress in Arntl-deficient male mice.
abstract: The basic helix-loop-helix transcription factor Aryl Hydrocarbon Receptor Nuclear Translocator-Like (ARNTL, also known as BMAL1 or MOP3) is a core component of the circadian timing system in mammals, which orchestrates 24-hour rhythms of physiology and behavior. Genetic ablation of Arntl in mice leads to behavioral and physiological arrhythmicity, including loss of circadian baseline regulation of glucocorticoids (GCs). GCs are important downstream regulators of circadian tissue clocks and have essential functions in the physiological adaptation to stress. The role of the clock machinery in the regulation of stress-induced GC release, however, is not well understood. Here we show that already under unstressed conditions Arntl-deficient mice suffer from hypocortisolism with impaired adrenal responsiveness to ACTH and down-regulated transcription of genes involved in cholesterol transport in adrenocortical cells. Under stress they show diminished GC and behavioral responses and develop behavioral resistance to acute and subchronic stressors, as shown using forced swim, tail suspension, and sucrose preference tests. These data suggest that the clock gene Arntl regulates circadian and acute secretion of GCs by the adrenal gland. Arntl disruption, probably via its effect on adrenal clock function, modulates stress axis activity and, thus, may promote resistance to both acute and repeated stress.
authors.affiliation: Chronophysiology Group (A.L., H.O.), Medical Department I, University of Lübeck, Lübeck, Germany; and Circadian Rhythms Group (A.L., A.S., J.H., H.O.), Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Alexei
authors.initials: A
authors.lastname: Leliavski
authors.forename: Anton
authors.initials: A
authors.lastname: Shostak
authors.forename: Jana
authors.initials: J
authors.lastname: Husse
authors.forename: Henrik
authors.initials: H
authors.lastname: Oster
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics* / Q000502:physiology; D000311:Adrenal Glands / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002940:Circadian Rhythm; D003345:Corticosterone / Q000378:metabolism; D003907:Dexamethasone / Q000737:chemistry; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism*; D006799:Housing, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D005082:Physical Exertion
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D005938:Glucocorticoids; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone