title: Elevated Hypothalamic Glucocorticoid Levels Are Associated With Obesity and Hyperphagia in Male Mice.
abstract: Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamic-pituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects. The Gc receptor (GR) is widely expressed throughout the body, including brain regions such as the hypothalamus. However, the extent to which chronic Gcs affect Gc concentrations in the hypothalamus and impact on GR and target genes is unknown. To investigate this, we used a murine model of corticosterone (Cort)-induced obesity and analyzed Cort levels in the hypothalamus and expression of genes relevant to Gc action. Mice were administered Cort (75 μg/mL) or ethanol (1%, vehicle) in drinking water for 4 weeks. Cort-treated mice had increased body weight, food intake, and adiposity. As expected, Cort increased plasma Cort levels at both zeitgeber time 1 and zeitgeber time 13, ablating the diurnal rhythm. Liquid chromatography dual tandem mass spectrometry revealed a 4-fold increase in hypothalamic Cort, which correlated with circulating levels and concentrations of Cort in other brain regions. This occurred despite decreased 11β-hydroxysteroid dehydrogenase (Hsd11b1) expression, the gene encoding the enzyme that regenerates active Gcs, whereas efflux transporter Abcb1 mRNA was unaltered. In addition, although Cort decreased hypothalamic GR (Nr3c1) expression 2-fold, the Gc-induced leucine zipper (Tsc22d3) mRNA increased, which indicated elevated GR activation. In keeping with the development of hyperphagia and obesity, Cort increased Agrp, but there were no changes in Pomc, Npy, or Cart mRNA in the hypothalamus. In summary, chronic Cort treatment causes chronic increases in hypothalamic Cort levels and a persistent elevation in Agrp, a mediator in the development of metabolic disturbances.
authors.affiliation: Faculty of Biology (C.S., E.H., A.D., T.-J.A., J.R.W., C.B.L., A.W.), Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Manchester Institute (H.S.), University of Manchester, Manchester M20 4BX, United Kingdom; and University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit (A.P.C.), Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Sefton
authors.affiliation: Faculty of Biology (C.S., E.H., A.D., T.-J.A., J.R.W., C.B.L., A.W.), Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Manchester Institute (H.S.), University of Manchester, Manchester M20 4BX, United Kingdom; and University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit (A.P.C.), Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Erika
authors.initials: E
authors.lastname: Harno
authors.affiliation: Faculty of Biology (C.S., E.H., A.D., T.-J.A., J.R.W., C.B.L., A.W.), Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Manchester Institute (H.S.), University of Manchester, Manchester M20 4BX, United Kingdom; and University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit (A.P.C.), Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Davies
authors.affiliation: Faculty of Biology (C.S., E.H., A.D., T.-J.A., J.R.W., C.B.L., A.W.), Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Manchester Institute (H.S.), University of Manchester, Manchester M20 4BX, United Kingdom; and University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit (A.P.C.), Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Small
authors.affiliation: Faculty of Biology (C.S., E.H., A.D., T.-J.A., J.R.W., C.B.L., A.W.), Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Manchester Institute (H.S.), University of Manchester, Manchester M20 4BX, United Kingdom; and University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit (A.P.C.), Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Tiffany-Jayne
authors.initials: TJ
authors.lastname: Allen
authors.affiliation: Faculty of Biology (C.S., E.H., A.D., T.-J.A., J.R.W., C.B.L., A.W.), Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Manchester Institute (H.S.), University of Manchester, Manchester M20 4BX, United Kingdom; and University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit (A.P.C.), Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Wray
authors.affiliation: Faculty of Biology (C.S., E.H., A.D., T.-J.A., J.R.W., C.B.L., A.W.), Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Manchester Institute (H.S.), University of Manchester, Manchester M20 4BX, United Kingdom; and University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit (A.P.C.), Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Lawrence
authors.affiliation: Faculty of Biology (C.S., E.H., A.D., T.-J.A., J.R.W., C.B.L., A.W.), Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Manchester Institute (H.S.), University of Manchester, Manchester M20 4BX, United Kingdom; and University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit (A.P.C.), Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Coll
authors.affiliation: Faculty of Biology (C.S., E.H., A.D., T.-J.A., J.R.W., C.B.L., A.W.), Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Manchester Institute (H.S.), University of Manchester, Manchester M20 4BX, United Kingdom; and University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit (A.P.C.), Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: White
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002853:Chromatography, Liquid; D004435:Eating / Q000187:drug effects; D005938:Glucocorticoids / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006963:Hyperphagia / Q000097:blood / Q000209:etiology*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000209:etiology*; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D005938:Glucocorticoids