Biological Actions of the Nutraceutical L-citrulline in Experimental Obesity

Abstract

AbstractL-citrulline is an organic α-amino acid supplement that has been shown to produce a number of salutary actions on whole-body physiology, which includes reducing muscle wasting and augmenting exercise/muscle performance. The latter has been suggested to arise from elevations in mitochondrial function. Because enhancing mitochondrial function has been proposed as a novel strategy to mitigate insulin resistance, our goal was to determine whether supplementation with L-citrulline also could improve glycemia in an experimental mouse model of obesity. We hypothesized that L-citrulline treatment would improve glycemia in obese mice, and this would be associated with elevations in skeletal muscle mitochondrial function. 10-week old C57BL/6J mice were fed either a low-fat (10% kcal from lard) or high-fat (60% kcal from lard) diet, while receiving drinking water supplemented with either vehicle or L-citrulline (100 mg/kg) for 15 weeks. Glucose homeostasis was assessed via glucose/insulin tolerance testing, while in vivo metabolism was assessed via indirect calorimetry, and forced exercise treadmill testing was utilized to assess endurance. As expected, obese mice supplemented with L-citrulline exhibited an increase in exercise capacity, which was associated with an improvement in glucose tolerance. Consistent with augmented mitochondrial biogenesis/function, we observed an increase in whole body oxygen consumption rates in obese mice supplemented with L-citrulline. Suprisingly, L-citrulline supplementation revealed a trend to worse insulin tolerance, and a trend to reduction in insulin signaling in obese mice. Taken together, although L-citrulline supplementation improves both glucose tolerance and exercise capacity in obese mice, one should exercise caution with its broad use as a nutraceutical due to potential deteriorations in insulin sensitivity.