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.
Coll
Anthony P
AP
Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2XY, UK.
Fassnacht
Martin
M
Klammer
Steffen
S
Hahner
Stephanie
S
Schulte
Dominik M
DM
Piper
Sarah
S
Tung
Y C Loraine
YC
Challis
Benjamin G
BG
Weinstein
Yacob
Y
Allolio
Bruno
B
O'Rahilly
Stephen
S
Beuschlein
Felix
F
D000311:Adrenal Glands / Q000187:drug effects* / Q000254:growth & development; D000324:Adrenocorticotropic Hormone / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D002452:Cell Count; D049109:Cell Proliferation; D004435:Eating / Q000187:drug effects*; D005260:Female; D015151:Immunoblotting / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000008:administration & dosage*; D011333:Pro-Opiomelanocortin / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism
D010446:Peptide Fragments; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone