|Robertson, Alan - PFIZER|
|Houseknecht, Karen - PFIZER|
Submitted to: Endocrine Society Meeting
Publication Type: Abstract Only
Publication Acceptance Date: April 24, 2003
Publication Date: June 19, 2003
Citation: Barb, C.R., Barrett, J.B., Kraeling, R.R., Robertson, A.S., Houseknecht, K.L. Intracerebroventricular injection of Melanocortin-3/4-Receptor (MC3/4-R) ligands in the pig: acute effects on feed intake and pituitary hormone secretion. Endocrine Society Annual Meeting. 2003. Abstract No. P1-205. Technical Abstract: A recently discovered class of receptors, MC3/4-R, are located within the brain and modulate feed intake in rodents. Stimulation of the receptor inhibits and blockade increases feed intake. Therefore, we conducted the follow experiments (EXP) in which treatments were administered to growing pigs intracerebroventricularly (ICV) in 150 ul of saline (S). EXP I, S (n = 4), 0.03 nM (n = 4), 0.3 nM. (n = 4) or 3 nM (n = 4) of MC4-R agonist, NDP-MSH; EXP II, fed + S (n = 3), fed + 10ug NDP-MSH (n = 3), fast + S (n = 4) and fast + 10ug NDP-MSH (n = 4). EXP III, S (n = 4), 0.01nM (n = 4), 0.1 nM (n = 4) or 1nM (n = 4) of MC3/4-R antagonist, SHU9119; EXP IV, S (n = 4), 3 nM (n = 4), or 6 nM (n = 4) of SHU9119; EXP V, S (n = 4), 0.1 ug (n = 4), 1.0 ug (n = 4),10 ug (n = 3) of agouti related peptide (AGRP); EXPVI, S (n = 4), 18.4 ug (n = 3), 36.9 ug (n = 4) or 73.8 ug (n = 4) AGRP and blood samples were collected via vena puncture and each animal genotyped for MC4-R polymorphs. After ICV treatment (time = 0), feed intake was monitored and blood samples collected every 15 min for 8 hr and assayed for GH and LH in EXP I, II and III. NDP-MSH suppressed (P <0.05) feed intake compared to controls at 12, 24, 48 and 72 hours after treatment. Fed pigs were more responsive to the MC3/4-R agonist than fasted animals. However, SHU9119 failed to stimulate intake but suppressed (P<0.05) intake by 48 hr except for the 1nM dose. The failure of MC3/4-R antagonist to stimulate feed intake suggests involvement of other brain hormone(s) which antagonize the action of SHU9119 at the MC3/4-R. Treatment with NDP-MSH or SHU9119 failed to affect LH and GH secretion, except the 10ug dose of NDP-MSH increased (P <0.05) GH secretion by 45 min after treatment and inhibited (P <0.05) GH secretion by hr 6 after ICV injection. Treatment with AGRP 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 a MC4-R gene missense mutation. It is possible that the MC4-R mutation alters MC4-R function and, thus, may explain the failure to demonstrate that MC3/4-R are involved in modulating feeding behavior and LH and GH secretion in the pig.