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Title: THE ROLE OF MELANOCORTIN-3/4-RECEPTOR IN REGULATING APPETITE, ENERGY HOMEOSTASIS AND NEUROENDOCRINE FUNCTION IN THE PIG

Author
item Barb, Claude
item ROBERTSON, A - PFIZER, INC.
item Barrett, John
item Kraeling, Robert
item HOUSEKNECHT, K - PFIZER, INC.

Submitted to: Journal of Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/20/2003
Publication Date: 4/1/2004
Citation: Barb, C.R., Robertson, A., Barrett, J.B., Kraeling, R.R., Houseknecht, K.L. 2004. The role of melanocortin-3/4-receptor in regulating appetite, energy homeostasis and neuroendocrine function in the pig. Journal of Endocrinology. 2004. v. 181. p. 39-52.

Interpretive Summary: A recently discovered class of receptors, melanocortin-3 and 4-receptor (MC3/4), are located within the brain and modulate feed intake in rodents. Stimulation of the receptor (agonist), inhibits feed intake where as blockade (antagonist) of the receptor increases intake. Our knowledge of factors regulating voluntary feed intake in humans and domestic animals is very limited. Administration of a MC3/4-receptor agonist suppressed feed intake. However, treatment with MC3/4-receptor antagonist failed to stimulate intake. The failure of MC3/4-receptor antagonist to stimulate feed intake suggests involvement of other brain hormone(s) which block the activity of the MC3/4-receptors. Treatment with agouti related peptide (AgRP), a natural brain hormone that blocks the MC3/4-receptor, failed to stimulate feed intake. These results do not support the idea that brain MC3/4-receptor pay a critical role in regulating feed intake in the pig. However, pigs expressed multiple mutations in the MC4-receptor gene. It is possible that the MC4-receptor mutation alters MC4-receptor activity and may explain the failure to demonstrate that the MC3/4-receptors are involved in modulating feeding behavior in the pig.

Technical Abstract: A recently discovered class of receptors, melanocortin-3 and 4-receptor (MC3/4), are located within the brain and modulate feed intake in rodents. Stimulation of the receptor (agonist), inhibits feed intake where as blockade (antagonist) of the receptor increases intake. Our knowledge of factors regulating voluntary feed intake in humans and domestic animals is very limited. Intracerebroventricula (ICV) administration of a MC3/4-receptor agonist, NDP, suppressed (P <0.05) feed intake compared to controls at 12, 24, 48 and 72 hours after treatment in growing pigs. Fed pigs were more responsive to the MC3/4-receptor agonist then fasted animals. However, ICV treatment with MC3/4-receptor antagonist, SHU, failed to stimulate intake. The failure of MC3/4-receptor antagonist to stimulate feed intake suggests involvement of other brain hormone(s) which antagonize the action of SHU at the MC3/4-receptors blocking its stimulatory effect on intake. Treatment with NDP or SHU9119 failed to effect LH and GH secretion. Treatment with agouti related peptide (AGRP), a natural brain hormone that blocks the MC3/4R, failed to stimulate feed intake. These results do not support the idea that endogenous melanocortin pays a critical role in regulating feed intake and pituitary hormone secretion in the pig. However, pigs were heterozygous for the MC4R gene mutation. It is possible that the MC4R mutation alters MC4R function and may explain the failure to demonstrate that the MC3/4-receptors are involved in modulating feeding behavior and LH and GH secretion in the pig.