Abstract | OBJECTIVE: METHODS: The actions of 20β-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding. RESULTS: 20β-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20β-DHB and absent in female mice with higher baseline adipose 20β-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding. CONCLUSIONS:
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Authors | Rachel M B Bell, Elisa Villalobos, Mark Nixon, Allende Miguelez-Crespo, Lee Murphy, Angie Fawkes, Audrey Coutts, Matthew G F Sharp, Martha V Koerner, Emma Allan, Onno C Meijer, Renè Houtman, Alex Odermatt, Katharina R Beck, Scott G Denham, Patricia Lee, Natalie Z M Homer, Brian R Walker, Ruth A Morgan |
Journal | Molecular metabolism
(Mol Metab)
Vol. 48
Pg. 101225
(06 2021)
ISSN: 2212-8778 [Electronic] Germany |
PMID | 33785425
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved. |
Chemical References |
- Glucocorticoids
- NR3C2 protein, human
- Receptors, Glucocorticoid
- Receptors, Mineralocorticoid
- 20-dihydrocorticosterone
- Alcohol Oxidoreductases
- carbonyl reductase 1, mouse
- Glucose
- Corticosterone
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Topics |
- Adipose Tissue
(metabolism)
- Alcohol Oxidoreductases
(genetics, metabolism)
- Animals
- Corticosterone
(analogs & derivatives, blood, pharmacology)
- Diet, High-Fat
(adverse effects)
- Disease Models, Animal
- Female
- Gene Knockdown Techniques
- Glucocorticoids
(metabolism)
- Glucose
(metabolism)
- Glucose Intolerance
(genetics, metabolism)
- HEK293 Cells
- Homeostasis
(genetics)
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Obesity
(genetics, metabolism)
- Receptors, Glucocorticoid
(metabolism)
- Receptors, Mineralocorticoid
(metabolism)
- Signal Transduction
(drug effects, genetics)
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