Obesity- and Sex-related Metabolism of Arginine and Nitric Oxide in Adults.BACKGROUND
 There is growing interest in the supplementation of arginine (Arg) and citrulline (Cit) in obesity due to their potential anti-obesogenic and anti-inflammatory properties.  However, there is no consensus on the metabolic changes in Arg kinetics in obesity.


 OBJECTIVE
 This exploratory cross-sectional study aimed to investigate the association between obesity, sex, and sex-by-obesity interaction on whole-body Arg kinetics in a large group of human subjects.


 We studied 83 non-obese (body mass index, BMI<30 kg/m2) and 80 morbidly obese (BMI>30 kg/m2) middle-aged individuals (40% males) enrolled in the MEDIT (MEtabolism of Disease with Isotope Tracers) trial.  After body composition measurement by dual-energy X-ray absorptiometry, we collected arterial(ized) blood samples for amino acid (AAs) concentrations, markers of inflammation (high-sensitivity C-reactive protein, hs-CRP), liver function, and glucose in a postabsorptive state.  We administered a pulse of AA stable tracers and measured whole-body productions (WBP) of Arg, Cit, ornithine (Orn), phenylalanine, and tyrosine, calculated their clearance (disposal capacity), and metabolites interconversions (markers for NO and de novo Arg production, systemic Arg hydrolysis, and whole-body protein breakdown, wbPB).  We measured plasma enrichments by LC-MS/MS and statistics by Fisher's exact test or analysis of (co)variance.  Significance at P<0.05.


 Obese individuals were normoglycemic and characterized by low-grade inflammation (P<0.0001) and greater wbPB (P=0.0298).  We found lower plasma Cit concentration (P<0.0001) in the obese group but no differences in the WBP of Arg, Cit, and Orn.  Furthermore, we observed overproduction of NO (P<0.0001) in obesity but lower de novo Arg production (P=0.0007).  The WBP of Arg was lower in females for almost all Arg-related amino acids, except for plasma Cit and NO production.


 CONCLUSIONS
 Further studies are needed to investigate if these changes could be related to factors such as increased Arg requirement in obesity or metabolic adaptation.Clinical Trial Registry: Trial registration ClinicalTrials.gov.  In the present paper, we report an analysis of the baseline measurements of healthy controls from the study numbers:NCT04461236 (URL: https://clinicaltrials.gov/ct2/show/NCT04461236),NCT02780206 (URL: https://clinicaltrials.gov/ct2/show/NCT02780206),NCT01787682 (URL: https://clinicaltrials.gov/ct2/show/NCT01787682),NCT02757638 (URL: https://clinicaltrials.gov/ct2/show/NCT02757638),NCT02770092 (URL: https://clinicaltrials.gov/ct2/show/NCT02770092),NCT02733120 (URL: https://clinicaltrials.gov/ct2/show/NCT02733120),NCT02780219 (URL: https://clinicaltrials.gov/ct2/show/NCT02780219).
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