Endocrine Abstracts

The primary function of brown adipose tissue (BAT) is to use lipids to generate heat through uncoupling of oxidative phosphorylation in mitochondria. Glucocorticoids (GC) have a negative effect upon BAT through inhibition of uncoupling protein 1 (UCP1) expression. Similarly, it has been reported that BAT levels decline with age and have been linked to age related accumulation of body fat, leading to the idea that improving BAT function during ageing could have a beneficial role in preventing weight gain due to its role in whole body energy expenditure. In this study we test the hypothesis that knock-out of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates active GC from inactive precursors, will have beneficial effects on the function of BAT, and that this beneficial effect will be magnified during ageing.

WT and global 11β-HSD1KO (GKO) mice were aged to either 15 weeks (young) or 100 weeks (aged) and BAT adipose tissue collected, weighed and analysed. Firstly, aged WT mice showed dramatically elevated 11β-HSD1 mRNA and protein compared to young mice. BAT mass and markers of differentiation and function were largely unchanged in young GKO compared to WT mice. However, the loss of 11β-HSD1 up-regulation in aged GKO mice resulted in a significant increase in BAT mass. Though histologically indistinguishable, GKO mice also had significantly enhanced mRNA expression of UCP1, PGC1a, PPARg, cox8b, and cox7a1 and at the protein level of UCP1. Further to this, GKO mice had a significantly increased number of mitochondria and blotting for electron transport chain complexes 1–5 identified increased expression of the NADH dehydrogenase 1β subcomplex subunit 8, succinate dehydrogenase iron-sulfur subunit compared to WT. These data demonstrate that abrogation of age associated 11β-HSD1 up-regulation and depletion of 11β-HSD1 mediated GC reactivation has a beneficial effect on markers of BAT function, highlighting the importance of 11β-HSD1 during BAT ageing.