Download PDF
Horm Metab Res 2001; 33(8): 480-485
DOI: 10.1055/s-2001-16941
Original Clinical
© Georg Thieme Verlag Stuttgart · New York

C-Terminal Fragments of ACTH Stimulate Feeding in Fasted Rats

K. A. Al-Barazanji1 , J. E. Miller1 , S. Q. J. Rice2 , J. R. S. Arch1 , J. K. Chambers1
  • 1 Department of Vascular Biology, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK
  • 2 Department of Gene Expression Sciences, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK
Further Information

Publication History

Publication Date:
04 September 2001 (online)

Also available at
    Permissions and Reprints

Peptides derived from pro-opiomelanocortin, including α-MSH and ACTH, play important roles in the regulation of feeding. We investigated the central effect of ACTH 1-39 (ACTH) and peptides derived from the N-terminus (ACTH 1-10, Acetyl-ACTH 1-13-amide [α-MSH]) and C-terminus (ACTH 18-39 and ACTH 22-39) of this peptide on feeding in 16 hour-fasted or rats fed ad libitum. As expected, ACTH reduced feeding in fed and previously fasted rats, although this anorectic effect was more pronounced in fasted rats. The N-terminal-derived peptide α-MSH, but not ACTH 1-10, reduced cumulative food intake over 2 h after its injection intracerebroventricularly (icv) in 16 h-fasted, but not in fed rats. In contrast, the C-terminal fragments produced a long-lasting increase in feeding in fasted, but not in fed rats. The anorectic effects of N-terminal fragments of ACTH are recognised to be mediated via melanocortin MC4 receptors. However, the orexigenic effects of the C-terminal fragments do not appear to be conducted via MC4 receptors, since neither ACTH 18-39 nor ACTH 22-39 stimulated cAMP accumulation nor inhibited the ACTH-stimulated cAMP accumulation in HEK-293 cells transfected with the recombinant MC4 receptor.

Key words:

Feeding - ACTH Fragments - MC4-R - cAMP

References

  • 1 Krieger D T, Liotta A, Brownstein M J. Presence of corticotropin in brain of normal and hypohysectomized rats.  Proc Natl Acad Sci USA. 1977;  74 648-652
    PubMedGoogle Scholar
  • 2 Civelli O, Birnberg N, Herbert E. Detection and quantitation of pro-opiomelanocortin mRNA in pituitary and brain tissues from different species.  J Biol Chem. 1982;  257 6783-6787
    PubMedGoogle Scholar
  • 3 Pilcher W H, Joseph S A. Co-localisation of CRF-ir perikarya and ACTH -ir fibers in rat brain.  Brain Res. 1984;  299 91-102
    CrossrefPubMedGoogle Scholar
  • 4 Wintzen M, Gilchrest B A. Proopiomelanocortin, its derived peptides, and the skin.  J Invest Dermatol. 1996;  106 3-10
    CrossrefPubMedGoogle Scholar
  • 5 Ottaviani E, Franchini A, Franceschi C. Pro-opiomelanocortin-derived peptides, cytokines, and nitric oxide in immune responses and stress: an evolutionary approach.  Int Rev Cytol. 1997;  170 79-141
    PubMedGoogle Scholar
  • 6 Denef C, Van Bael A. A new family of growth and differentiation factors derived from the N-terminal domain of proopiomelanocortin (N-POMC).  Comp Biochem Physiol. 1998;  119 317-324
    PubMedGoogle Scholar
  • 7 Castro M G, Morrison E. Post-translational processing of proopiomelanocortin in the pituitary and in the brain.  Crit Rev Neurobiol. 1977;  11 35-57
    PubMedGoogle Scholar
  • 8 Yaswen L, Diehl N, Brennan M B, Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to melanocortin.  Nature Med. 1999;  5 1066-1070
    CrossrefPubMedGoogle Scholar
  • 9 Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans.  Nature Genet. 1998;  19 155-157
    CrossrefPubMedGoogle Scholar
  • 10 Poggioli R, Vergoni A V, Bertolini A. ACTH-(1-24) and alpha-MSH antagonize feeding behaviour stimulated by kappa opiate agonists.  Peptides. 1986;  7 843-848
    CrossrefPubMedGoogle Scholar
  • 11 Vergoni A V, Poggioli R, Marrama D, Bertolini A. Inhibition of feeding by ACTH-(1-24): behavioural and pharmacological aspects.  Eur J Pharmacol. 1990;  179 347-355
    CrossrefPubMedGoogle Scholar
  • 12 Bailey C J, Flatt P R. Insulin releasing effects of adrenocorticotropin (ACTH 1-39) and ACTH fragments (1-24 and 18-39) in lean and genetically obese hyperglycaemic (ob/ob) mice.  Int J Obes. 1987;  11 175-181
    PubMedGoogle Scholar
  • 13 Bertolini A, Guarini S, Rompianesi E, Ferrari W. Alpha-MSH and other ACTH fragments improve cardiovascular function and survival in experimental hemorrhagic shock.  Eur J Pharmacol. 1986;  130 19-26
    CrossrefPubMedGoogle Scholar
  • 14 Cort J H, Cort J, Novakova J, Skopkova J. Interaction of vasopressins and linear N-terminal ACTH fragments in the induction of natriuresis.  Eur J Clin Invest. 1974;  4 293-298
    PubMedGoogle Scholar
  • 15 van Riezen H, Rigter H, De Wied D. Possible significance of ACTH fragments for human mental performance.  Behav Biol. 1977;  20 311-324
    CrossrefPubMedGoogle Scholar
  • 16 Martin J T, van Wimersma Greidanus T B. Imprinting behaviour: influence of vasopressin and ACTH analogues.  Psychneuroendocrinology. 1979;  3 261-269
    PubMedGoogle Scholar
  • 17 Pranzatelli M R. Review on the molecular mechanism of adrenocorticotrophic hormone in the CNS: neurotransmitters and receptors.  Exp Neurol. 1994;  125 142-161
    CrossrefPubMedGoogle Scholar
  • 18 Paxinos G, Watson C. The rat brain in stereotaxic co-ordinates.  New York:; Academic Press, 1986 2nd Ed.
    Google Scholar
  • 19 Sawyer T K, Sanfilippo P J, Hruby V J, Engel M H, Heward C B, Burnett J B, Hadley M E. 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity.  Proc Natl Acad Sci USA. 1980;  77 5754-5758
    PubMedGoogle Scholar
  • 20 Quillan J M, Sadee W, Wei E T, Jimenez C, Ji L, Chang J K. A synthetic human Agouti-related protein-(83-132)-NH2 fragment is a potent inhibitor of melanocortin receptor function.  FEBS Lett. 1998;  428 59-62
    CrossrefPubMedGoogle Scholar
  • 21 Smith E M, Brosnan P, Meyer W J, Blalock J E. An ACTH receptor on human mononuclear leukocytes. Relation to adrenal ACTH-receptor activity.  N Engl J Med. 1987;  317 1266-1269
    PubMedGoogle Scholar
  • 22 Lefkowitz R J, Roth J, Pricer W, Pastan I. ACTH receptors in the adrenal: specific binding of ACTH-125I and its relation to adenyl cyclase.  Proc Natl Acad Sci USA. 1970;  64 745-752
    PubMedGoogle Scholar
  • 23 Oelofsen W, Ramachandran J. Studies of corticotropin receptors on rat adipocytes.  Arch Biochem Biophys. 1983;  225 414-421
    CrossrefPubMedGoogle Scholar
  • 24 Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Watson S J, DelValle J, Yamada T. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor.  J Biol Chem. 1993;  268 15 174-15 179
    PubMedGoogle Scholar
  • 25 Tatro J B. Melanotropin receptors in the brain are differentially distributed and recognize both corticotropin and α-melanocyte stimulating hormone.  Brain Res. 1990;  536 124-132
    CrossrefPubMedGoogle Scholar
  • 26 Tatro J B. Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides.  Neuroimmunomodulation. 1996;  3 259-284
    PubMedGoogle Scholar
  • 27 Huszar D, Lynch C A, Fairchild-Huntress V, Dunmore J H, Fang Q, Berkemeier L R, Gu W, Kesterson R A, Boston B A, Cone R D, Smith F J, Campfield L A, Burn P, Lee F. Targeted disruption of the melanocortin-4 receptor results in obesity in mice.  Cell. 1997;  88 131-141
    CrossrefPubMedGoogle Scholar
  • 28 Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, Watson S J, DelValle J, Yamada T. Molecular cloning of a novel melanocortin receptor.  J Biol Chem. 1993;  268 8246-8250
    PubMedGoogle Scholar
  • 29 Rossi M, Kim M S, Morgan D GA, Small C J, Edwards C MB, Sunter D, Abusnana S, Goldstone A P, Russell S H, Stanley S A, Smith D M, Yagaloff K, Ghatei M A, Bloom S R. A C-terminal fragment of agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo.  Endocrinology. 1998;  139 4428-4431
    CrossrefPubMedGoogle Scholar
  • 30 Stanley B G, Leibowitz S F. Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus.  Life Sci. 1984;  35 2635-2642
    CrossrefPubMedGoogle Scholar
  • 31 Kyrkouli S E, Stanley B G, Leibowitz S F. Galanin: stimulation of feeding induced by medial hypothalamic injection of this novel peptide.  Eur J Pharmacol. 1986;  122 159-160
    CrossrefPubMedGoogle Scholar
  • 32 Rossi M, Choi S J, O’Shea D, Miyoshi T, Ghatei M A, Bloom S R. Melanin concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight.  Endocrinology. 1997;  138 351-355
    CrossrefPubMedGoogle Scholar
  • 33 Haynes A C, Jackson B, Overend P, Buckingham R E, Wilson S, Tadayyon M, Arch J RS. Effects of single and chronic icv administration of the orexins on feeding in the rat.  Peptides. 1999;  20 1099-1105
    CrossrefPubMedGoogle Scholar
  • 34 Ninan I, Kulkarni S K. Dopamine receptor sensitive effect of dizocilpine on feeding behaviour.  Brain Res. 1998;  812 157-163
    CrossrefPubMedGoogle Scholar

Dr. K. A. Al-Barazanji

Department of Metabolic Diseases
GSK Pharmaceuticals

RTP, NC27709
USA


Phone: + 1 (919) 483 4447

Fax: + 1 (919) 483 3777

Email: Kaa9753@gsk.com

      >