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.