Biological basis of the ractopamine response

Abstract

The potential for beta-adrenergic receptor (βAR) agonists to modify growth rate and body composition has been investigated for over 20 yr. Ractopamine was developed by Elanco Animal Health and is the first βAR ligand to be cleared for use in pigs in the United States, which occurred in 2000. Ractopamine is structurally similar to the natural catecholamines epinephrine and norepinephrine and binds with high affinity to βAR in pig adipose and muscle tissue. The family of βAR, however, belongs to a much larger family of structurally related G-protein coupled receptors (GPCR) and there is little or no information available as to whether ractopamine binds and signals through additional GPCR. The question of whether βARmediate the growth response in pigs and other animals is not fully settled, but primary attention has been given to understanding how βAR might mediate increased growth and protein accretion, and whether effects are direct on adipose and muscle tissue or mediated by secondary factors. Ractopamine is a racemic mixture of four isomers resulting from two asymmetric carbons. The RR isomer (levorotatory at both carbons) has the highest affinity for the pig β1AR and β2AR and Kd values are essentially equivalent for both subtypes (∼25 nM). Other isomers have from 3- to 600-fold lower affinity. The RR isomer appears to mediate the growth response in rats and likely is the active isomer in pigs. Therefore, ractopamine can be considered nonselective in binding to either the β1AR or β2AR in pigs. It is not known, however, whether the β3AR or additional subtypes may mediate a ractopamine response. Direct activation of βAR in adipocytes promotes triglyceride hydrolysis and decreases fatty acid and triglyceride synthesis, thus leading to less lipid accumulation. Fat accretion in pigs given ractopamine is not consistently reduced, which may result from βAR down-regulation. Ractopamine consistently increases muscle protein accretion in pigs. Responses are maximal within the 1st wk and decline toward zero over 4 to 6 wk. Curiously, βAR down-regulation is not significant in skeletal muscle. The mechanism responsible for increased protein accretion is not clear, but cumulative evidence points to a direct effect, possibly involving both protein synthesis and degradation.