Supplemental citrulline is more efficient than arginine to increase systemic arginine availability in mice

Authors: AGARWAL, UMANG - Children'S Nutrition Research Center (CNRC); DIDELIJA, INKA - Children'S Nutrition Research Center (CNRC); YUAN, YANG - Children'S Nutrition Research Center (CNRC); WANG, XIAOYING - Children'S Nutrition Research Center (CNRC); MARINI, JUAN - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/17/2017
Publication Date: 4/1/2017
Citation: Agarwal, U., Didelija, I.C., Yuan, Y., Wang, X., Marini, J.C. 2017. Supplemental citrulline is more efficient than arginine to increase systemic arginine availability in mice. Journal of Nutrition. 147(4):596-602.

Interpretive Summary: The amino acid, arginine, has many functions in the body and in situations of great demand, like growth or disease, additional arginine is needed. Thus, supplementation with arginine seems to be the obvious choice to meet increased demand. However, a large fraction of arginine disappears during absorption as well as in the liver, before arginine can reach the peripheral circulation. Here we have shown that citrulline, the immediate precursor for the synthesis of arginine, is not utilized during absorption nor by the liver and that 100% reaches the peripheral circulation. Citrulline is then utilized to make arginine in the body. For this reason supplemental citrulline is more efficient at providing arginine than arginine supplementation.

Technical Abstract: Arginine is considered an essential amino acid in various (patho)physiological conditions of high demand. However, dietary arginine supplementation (ARG) suffers various drawbacks, including extensive first-pass extraction. Citrulline supplementation (CIT) may be a better alternative than arginine, as its only fate in vivo is conversion into arginine. The goal of the present research is to determine the relative efficiency of arginine and citrulline supplementation to improve arginine availability. Six week-old C57BL/6J male mice fitted with gastric catheters were adapted to one of 7 experimental diets for 2 weeks. The basal diet contained 2.5 g L-arginine/kg, whereas the supplemented diets contained additional 2.5, 7.5 and 12.5 g/kg diet of either L-arginine or L-citrulline. On the final day after a 3h fast, mice were continuously infused intragastrically with an elemental diet similar to the dietary treatment, along with L-[13C6]arginine to determine the first-pass splanchnic metabolism (FPM) of arginine. In addition, tracers were continuously infused intravenously to determine the fluxes and interconversions between citrulline and arginine. Linear regression slopes were compared to determine the relative efficiency of each supplement. Whereas all the supplemented citrulline (105+/-7%) appeared in plasma and resulted in a marginal increase of 86% in the arginine flux, supplemental arginine underwent ~70% FPM, indicating that only 30% of the supplemental arginine entered the peripheral circulation. However, supplemental arginine did not increase arginine flux. Both supplements linearly increased (P<0.01) plasma arginine concentration from 109 umol/L for the basal diet to 159 and 214 umol/L for the highest ARG and CIT levels, respectively. However, supplemental citrulline increased arginine concentrations to a greater (P<0.01) extent. Citrulline supplementation is more efficient at increasing arginine availability than arginine supplementation itself in the mouse model studied.