Endocrine Abstracts (2006) 11 P387

Androgen regulation of hepatic glucocorticoid metabolism in obese Zucker rats

DEW Livingstone1, P Barat2, CR McDonnell1, BR Walker1 & R Andrew1

1University of Edinburgh, Edinburgh, United Kingdom; 2Institut François Magendie, Bordeaux, France.

Obesity is associated with decreased hepatic reactivation of glucocorticoids (Gc) by 11β-hydroxysteroid dehydrogenase type 1 (11HSD) and increased metabolism of glucocorticoids by hepatic A-ring reductases, which may contribute to activation of the hypothalamic-pituitary-adrenal axis. Androgen action encourages central obesity and increased metabolic complications, possibly by altering Gc metabolism.

This study investigates the role of gonadal androgens in the dysregulation of hepatic glucocorticoid metabolism in obese Zucker rats.

Lean (L) and Obese (O) Zucker rats (9wks, n=10/group) were studied 3wks after gonadectomy (GDX) or sham surgery (SH). Hepatic 11HSD and 5β-reductase activities were measured by conversion of [3H]4-corticosterone (pmol/hr/mg protein) and mRNA for 11HSD1, 5β- and 5α-reductases, and 3α-HSD measured by real-time PCR, corrected for cyclophilin A and 18S endogenous controls (AU). *Denotes P<0.05, and **P<0.01.

As reported previously, in obese rats hepatic 11HSD was lower (*), 5α- and 5β-reductase higher (**) and 3αHSD not different (P=0.5) compared with lean rats (see table). GDX decreased 11HSD activity and mRNA (**) in lean and obese rats, whereas 5β-reducase was increased only in obese rats (**). GDX increased 5α-reductase 1 (**) and 3α-HSD (*) mRNA in lean and obese rats. Furthermore GDX increased adrenal mass in lean (58±3 v 50±4 mg**) and obese (56±4 v 46±3 mg **) rats.

Table 1
11HSD activity11HSD mRNA5β-R Activity5β-R mRNA5α-R mRNA3αHSD mRNA
L-GDX 66±70.6±0.19±10.8±0.11.1±0.10.7±0.1

In conclusion, while androgens exert potent effects on glucocorticoid metabolism and adrenal mass, removal of gonadal androgens exacerbates, rather than ameliorates, changes in hepatic glucocorticoid metabolism in obese Zucker rats.

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