Glucocorticoids act on several major neuropeptide networks in the hypothalamus which are important for regulation of energy balance and insulin sensitivity. Active glucocorticoids (cortisol/corticosterone in humans/rodents) can be regenerated from their inactive forms by the enzyme 11β-hydroxysteroid dehydrogenase type one (11β-HSD1) which is expressed in the hypothalamus. Therefore we decreased 11β-HSD1 expression in the brain to investigate the role of regenerated corticosterone on metabolic parameters.
Knock-down of 11β-HSD1 in the CNS (BKO) using a Nestin-Cre promoter led to >90% inhibition of 11β-HSD1 activity and expression in the brain. Twelve-week-old BKO, 11β-HSD1 conditional (floxed) and Nestin-Cre mice were placed on high fat diet (HFD) for 12 weeks. The BKOs were lighter than the floxed mice, but similar to the Nestin-Cre mice. There was no difference in % body fat measured by dual energy X-ray absorptiometry (DXA; Nestin-Cre: 41.5±1.7 vs BKO: 39.4±2.6 vs floxed: 38.7±6.2) or fat distribution. BKO had a reduced food intake compared to floxed animals, but higher food intake than Nestin-Cre. Although decreased glucocorticoids in the hypothalamus would be expected to improve insulin sensitivity, BKO and Nestin-Cre mice had similar insulin sensitivity measured during an oral glucose tolerance test (OGTT) with the floxed mice tending to be less insulin sensitive. Glucose responses were not different between any of the three strains. Reduction of glucocorticoids in the brain, may be expected to upregulate the hypothalamic-pituitary-adrenal axis through reduction in negative feedback, however, there was no difference in adrenal gland weight between the three strains (BKO: 2.3±0.6 vs nestin-Cre: 2.2±0.4 vs floxed: 2.6±0.7 mg).
In summary, 11β-HSD1 knockdown in the brain does not improve the metabolic effects of HFD. This suggests that 11ßHSD1 inhibition in brain is unlikely to be a primary driver of efficacy in the search for11β-HSD1 inhibitors to treat type two diabetes and obesity.
Declaration of interest
JDS and AVT are employees of Astrazeneca. JDS, AVT and BL are shareholders of AstraZeneca. EH and AW recieve grant funsing from AstraZeneca
Declaration of funding: This work is supported by funding from AstraZeneca (E H and A W).