Adrenal 20alpha-hydroxysteroid dehydrogenase in the mouse catabolizes progesterone and 11-deoxycorticosterone and is restricted to the X-zone.

The enzyme 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) is a progesterone-catabolizing enzyme that is highly expressed in mouse ovaries and adrenals. Although the functional significance of ovarian 20alpha-HSD for the induction of parturition has been defined, regulation and distribution of 20alpha-HSD in the adrenal gland has not been determined. We demonstrate that the expression of adrenal 20alpha-HSD is restricted to the X-zone, a transient zone between the adrenal cortex and the medulla of yet unknown function. Adrenal 20alpha-HSD activity in male mice peaks at 3 wk of age and disappears thereafter, whereas 20alpha-HSD enzyme activity is maintained in adrenals from nulliparous female animals. Testosterone treatment of female mice induces rapid involution of the X-zone that is associated with the disappearance of the 20alpha-HSD-positive cells. Conversely, reappearance of 20alpha-HSD expression and activity in male animals is evident after gonadectomy. Moreover, pregnancy, but not pseudopregnancy, is accompanied by X-zone regression and loss of 20alpha-HSD activity. Pregnancy-induced X-zone regression and -abolished 20alpha-HSD expression is partially restored in animals that were kept from nursing their pups. We found that in addition to its progesterone-reducing activity, 20alpha-HSD also functions as an 11-deoxycorticosterone-catabolizing enzyme. The unaltered growth kinetics of the X-zone in 20alpha-HSD knockout animals suggests that 20alpha-HSD is not required for the regulation of X-zone growth. However, 20alpha-HSD expression and enzymatic activity in all experimental paradigms is closely correlated with the presence of the X-zone. These findings provide the basis for 20alpha-HSD as a reliable marker of the murine X-zone.

Peripheral administration of the N-terminal pro-opiomelanocortin fragment 1-28 to Pomc-/- mice reduces food intake and weight but does not affect adrenal growth or corticosterone production.

Pro-opiomelanocortin (POMC) is a polypeptide precursor that undergoes extensive processing to yield a range of peptides with biologically diverse functions. POMC-derived ACTH is vital for normal adrenal function and the melanocortin alpha-MSH plays a key role in appetite control and energy homeostasis. However, the roles of peptide fragments derived from the highly conserved N-terminal region of POMC are less well characterized. We have used mice with a null mutation in the Pomc gene (Pomc(-/-)) to determine the in vivo effects of synthetic N-terminal 1-28 POMC, which has been shown previously to possess adrenal mitogenic activity. 1-28 POMC (20 mug) given s.c. for 10 days had no effect on the adrenal cortex of Pomc(-/-) mice, with resultant cortical morphology and plasma corticosterone levels being indistinguishable from sham treatment. Concurrent administration of 1-28 POMC and 1-24 ACTH (30 mug/day) resulted in changes identical to 1-24 ACTH treatment alone, which consisted of upregulation of steroidogenic enzymes, elevation of corticosterone levels, hypertrophy of the zona fasciculate, and regression of the X-zone. However, treatment of corticosterone-depleted Pomc(-/-) mice with 1-28 POMC reduced cumulative food intake and total body weight. These anorexigenic effects were ameliorated when the peptide was administered to Pomc(-/-) mice with circulating corticosterone restored either to a low physiological level by corticosterone-supplemented drinking water (CORT) or to a supraphysiological level by concurrent 1-24 ACTH administration. Further, i.c.v. administration of 1-28 POMC to CORT-treated Pomc(-/-) mice had no effect on food intake or body weight. In wild-type mice, the effects of 1-28 POMC upon food intake and body weight were identical to sham treatment, but 1-28 POMC was able to ameliorate the hyperphagia induced by concurrent 1-24 ACTH treatment. In a mouse model which lacks all endogenous POMC peptides, s.c. treatment with synthetic 1-28 POMC alone can reduce food intake and body weight, but has no impact upon adrenal growth or steroidogenesis.