Endocrine Abstracts

Deficiency of the intracellular glucocorticoid (GC) reactivating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) invokes compensatory activation of the HPA axis. Nevertheless, 11β-HSD1^−/− mice resist dietary-induced obesity indicating that target tissues are protected from GC actions. Since endocrine adaptation to diet is mediated by altered HPA activity, we investigated whether the adrenal response to high fat (HF) diet is compromised in 11β-HSD1^−/− mice.

Control and null male mice (n=5) were fed normal or HF diet whilst being infused sc with bromodeoxy-uridine (BrdU) to mark cell proliferation. After 2 weeks, tissues and blood were collected. HF diet and 11β-HSD1^−/− genotype increased adrenal mass by 10 and 20% (P<0.01). Mid-sections of adrenal glands were stained immunocytochemically for BrdU. Cell size and percentages of BrdU+ve nuclei were measured in the aldosterone-synthesizing zona glomerulosa and the GC-synthesizing zonae fasciculata and reticularis. HF diet increased cell size by 45% in null but not control mice (P<0.01). BrdU labelling was highest in the glomerulosa and declined by 90% in the reticularis; labelling in the medulla was also low. HF diet and 11β-HSD1^−/− genotype increased percentages of labelled cells by 2.5 fold in the glomerulosa and fasciculata (P<0.001). Plasma renin and steroid concentrations were measured by radioimmunoassay. Neither diet nor genotype affected corticosterone. HF diet raised renin by 50% and reduced aldosterone by 40% (P<0.05); the aldosterone:renin ratio was reduced from 1.11±0.15 to 0.33±0.08.

We conclude that resistance to obesity in 11β-HSD1^−/− mice is not due to insufficient adrenal corticosterone production. Both HF diet and 11β-HSD1 inactivation caused adrenal hypertrophy. Hyperplasia of glomerulosa cells is probably due to HPA activation and as well as increased renin. Glomerulosa and renin changes were associated with decreased rather than increased plasma aldosterone indicating a novel mechanism of aldosterone clearance that is secondarily influenced by glucocorticoid metabolism.