Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1.

Hdl Handle:
http://hdl.handle.net/10147/253940
Title:
Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1.
Authors:
Lavery, Gareth G; Zielinska, Agnieszka E; Gathercole, Laura L; Hughes, Beverly; Semjonous, Nina; Guest, Phillip; Saqib, Khalid; Sherlock, Mark; Reynolds, Gary; Morgan, Stuart A; Tomlinson, Jeremy W; Walker, Elizabeth A; Rabbitt, Elizabeth H; Stewart, Paul M
Affiliation:
Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom. g.g.lavery@bham.ac.uk
Citation:
Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1. 2012, 153 (7):3236-48 Endocrinology
Publisher:
Endocrinology
Journal:
Endocrinology
Issue Date:
Jul-2012
URI:
http://hdl.handle.net/10147/253940
DOI:
10.1210/en.2012-1019
PubMed ID:
22555437
Abstract:
Glucocorticoids (GC) are implicated in the development of metabolic syndrome, and patients with GC excess share many clinical features, such as central obesity and glucose intolerance. In patients with obesity or type 2 diabetes, systemic GC concentrations seem to be invariably normal. Tissue GC concentrations determined by the hypothalamic-pituitary-adrenal (HPA) axis and local cortisol (corticosterone in mice) regeneration from cortisone (11-dehydrocorticosterone in mice) by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, principally expressed in the liver. Transgenic mice have demonstrated the importance of 11β-HSD1 in mediating aspects of the metabolic syndrome, as well as HPA axis control. In order to address the primacy of hepatic 11β-HSD1 in regulating metabolism and the HPA axis, we have generated liver-specific 11β-HSD1 knockout (LKO) mice, assessed biomarkers of GC metabolism, and examined responses to high-fat feeding. LKO mice were able to regenerate cortisol from cortisone to 40% of control and had no discernible difference in a urinary metabolite marker of 11β-HSD1 activity. Although circulating corticosterone was unaltered, adrenal size was increased, indicative of chronic HPA stimulation. There was a mild improvement in glucose tolerance but with insulin sensitivity largely unaffected. Adiposity and body weight were unaffected as were aspects of hepatic lipid homeostasis, triglyceride accumulation, and serum lipids. Additionally, no changes in the expression of genes involved in glucose or lipid homeostasis were observed. Liver-specific deletion of 11β-HSD1 reduces corticosterone regeneration and may be important for setting aspects of HPA axis tone, without impacting upon urinary steroid metabolite profile. These discordant data have significant implications for the use of these biomarkers of 11β-HSD1 activity in clinical studies. The paucity of metabolic abnormalities in LKO points to important compensatory effects by HPA activation and to a crucial role of extrahepatic 11β-HSD1 expression, highlighting the contribution of cross talk between GC target tissues in determining metabolic phenotype.
Item Type:
Article
Language:
en
MeSH:
11-beta-Hydroxysteroid Dehydrogenase Type 1; Alleles; Animals; Biological Markers; Cortisone; Gene Expression Regulation, Enzymologic; Glucocorticoids; Hydrocortisone; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microsomes, Liver; Phenotype
ISSN:
1945-7170

Full metadata record

DC FieldValue Language
dc.contributor.authorLavery, Gareth Gen_GB
dc.contributor.authorZielinska, Agnieszka Een_GB
dc.contributor.authorGathercole, Laura Len_GB
dc.contributor.authorHughes, Beverlyen_GB
dc.contributor.authorSemjonous, Ninaen_GB
dc.contributor.authorGuest, Phillipen_GB
dc.contributor.authorSaqib, Khaliden_GB
dc.contributor.authorSherlock, Marken_GB
dc.contributor.authorReynolds, Garyen_GB
dc.contributor.authorMorgan, Stuart Aen_GB
dc.contributor.authorTomlinson, Jeremy Wen_GB
dc.contributor.authorWalker, Elizabeth Aen_GB
dc.contributor.authorRabbitt, Elizabeth Hen_GB
dc.contributor.authorStewart, Paul Men_GB
dc.date.accessioned2012-11-29T15:09:07Z-
dc.date.available2012-11-29T15:09:07Z-
dc.date.issued2012-07-
dc.identifier.citationLack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1. 2012, 153 (7):3236-48 Endocrinologyen_GB
dc.identifier.issn1945-7170-
dc.identifier.pmid22555437-
dc.identifier.doi10.1210/en.2012-1019-
dc.identifier.urihttp://hdl.handle.net/10147/253940-
dc.description.abstractGlucocorticoids (GC) are implicated in the development of metabolic syndrome, and patients with GC excess share many clinical features, such as central obesity and glucose intolerance. In patients with obesity or type 2 diabetes, systemic GC concentrations seem to be invariably normal. Tissue GC concentrations determined by the hypothalamic-pituitary-adrenal (HPA) axis and local cortisol (corticosterone in mice) regeneration from cortisone (11-dehydrocorticosterone in mice) by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, principally expressed in the liver. Transgenic mice have demonstrated the importance of 11β-HSD1 in mediating aspects of the metabolic syndrome, as well as HPA axis control. In order to address the primacy of hepatic 11β-HSD1 in regulating metabolism and the HPA axis, we have generated liver-specific 11β-HSD1 knockout (LKO) mice, assessed biomarkers of GC metabolism, and examined responses to high-fat feeding. LKO mice were able to regenerate cortisol from cortisone to 40% of control and had no discernible difference in a urinary metabolite marker of 11β-HSD1 activity. Although circulating corticosterone was unaltered, adrenal size was increased, indicative of chronic HPA stimulation. There was a mild improvement in glucose tolerance but with insulin sensitivity largely unaffected. Adiposity and body weight were unaffected as were aspects of hepatic lipid homeostasis, triglyceride accumulation, and serum lipids. Additionally, no changes in the expression of genes involved in glucose or lipid homeostasis were observed. Liver-specific deletion of 11β-HSD1 reduces corticosterone regeneration and may be important for setting aspects of HPA axis tone, without impacting upon urinary steroid metabolite profile. These discordant data have significant implications for the use of these biomarkers of 11β-HSD1 activity in clinical studies. The paucity of metabolic abnormalities in LKO points to important compensatory effects by HPA activation and to a crucial role of extrahepatic 11β-HSD1 expression, highlighting the contribution of cross talk between GC target tissues in determining metabolic phenotype.en_GB
dc.language.isoenen
dc.publisherEndocrinologyen_GB
dc.rightsArchived with thanks to Endocrinologyen_GB
dc.subject.mesh11-beta-Hydroxysteroid Dehydrogenase Type 1-
dc.subject.meshAlleles-
dc.subject.meshAnimals-
dc.subject.meshBiological Markers-
dc.subject.meshCortisone-
dc.subject.meshGene Expression Regulation, Enzymologic-
dc.subject.meshGlucocorticoids-
dc.subject.meshHydrocortisone-
dc.subject.meshLiver-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshMice, Knockout-
dc.subject.meshMice, Transgenic-
dc.subject.meshMicrosomes, Liver-
dc.subject.meshPhenotype-
dc.titleLack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1.en_GB
dc.typeArticleen
dc.contributor.departmentCentre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom. g.g.lavery@bham.ac.uken_GB
dc.identifier.journalEndocrinologyen_GB
dc.description.provinceLeinsteren

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