11β-HSD1 contributes to age-related metabolic decline in male mice

Abstract

The aged phenotype shares several metabolic similarities with that of circulatory glucocorticoid excess (Cushing's syndrome), including type 2 diabetes, obesity, hypertension, and myopathy. We hypothesise that local tissue generation of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts 11-dehydrocorticosterone to active corticosterone in rodents (corticosterone to cortisol in man), plays a role in driving age-related chronic disease. In this study, we have examined the impact of ageing on glucocorticoid metabolism, insulin tolerance, adiposity, muscle strength, and blood pressure in both wildtype (WT) and transgenic male mice with a global deletion of 11β-HSD1 (11β-HSD1-/-) following 4 months high-fat feeding. We found that high fat-fed 11β-HSD1-/- mice were protected from age-related glucose intolerance and hyperinsulinemia when compared to age/diet-matched WTs. By contrast, aged 11β-HSD1-/- mice were not protected from the onset of sarcopenia observed in the aged WTs. Young 11β-HSD1-/- mice were partially protected from diet-induced obesity; however, this partial protection was lost with age. Despite greater overall obesity, the aged 11β-HSD1-/- animals stored fat in more metabolically safer adipose depots as compared to the aged WTs. Serum analysis revealed both WT and 11β-HSD1-/- mice had an age-related increase in morning corticosterone. Surprisingly, 11β-HSD1 oxo-reductase activity in the liver and skeletal muscle was unchanged with age in WT mice and decreased in gonadal adipose tissue. These data suggest that deletion of 11β-HSD1 in high fat-fed, but not chow-fed, male mice protects from age-related insulin resistance and supports a metabolically favourable fat distribution.

Publication DOI: https://doi.org/10.1530/JOE-22-0169
Divisions: College of Health & Life Sciences > Aston Medical School
Funding Information: This work has been supported by the Wellcome Trust (program grant ref. 082809) (P M S) and the ERC Advanced Research Grant (PRECORT) (P M S).
Additional Information: This work is licensed under a Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0/
Uncontrolled Keywords: 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics,Animals,Corticosterone/metabolism,Diabetes Mellitus, Type 2,Glucocorticoids/metabolism,Hydrocortisone,Insulin,Male,Mice,Mice, Transgenic,Obesity/genetics
Publication ISSN: 1479-6805
Last Modified: 27 Nov 2024 08:19
Date Deposited: 31 Jan 2024 14:53
Full Text Link:
Related URLs: https://joe.bio ... JOE-22-0169.xml (Publisher URL)
PURE Output Type: Article
Published Date: 2022-12-01
Published Online Date: 2022-10-07
Accepted Date: 2022-09-12
Authors: Morgan, Stuart A
Gathercole, Laura L
Hassan-Smith, Zaki K (ORCID Profile 0000-0002-8387-3039)
Tomlinson, Jeremy
Stewart, Paul M
Lavery, Gareth G

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