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The protein-energy malnutrition that affects a part of the elderly people accentuates their muscular decline (sarcopenia and dynapenia) and thus increases the morbimortality. Malnutrition prevention and treatment seem to be difficult due to the defect in elderly response to renutrition with results remaining rather disappointing. However, recent scientific data suggest that an amino acid could be particularly promising: L-citrulline. Indeed, this amino acid is a powerful stimulant to muscular protein synthesis. In a pivotal work carried out in old rats with malnutrition, an oral supply of citrulline (5 days) allows increasing the muscular protein content (+20%) and synthesis (+90%). More recently, it was shown that this action of the citrulline was durable over time; a chronic supply of citrulline (3 months) in healthy old rats results in 25% increase in the muscle mass. Otherwise, the supply of citrulline is accompanied by an improvement of the muscle mass and functional capacities (muscle force and motility). These experimental findings have also been demonstrated in humans; an oral supply of citrulline leads to about 25% increase of muscle protein synthesis in healthy volunteers. So, the administration of citrulline could be an effective and innovating nutritional strategy to limit the muscular decline with aging. By preventing the protein-energy malnutrition in elderly people, citrulline administration could delay the dependency, improve quality of life, and limit morbi-mortality related to dynapenia. © La Revue de Gérlatile.

Joffin N.,University of Paris Descartes | Joffin N.,Institute National Of La Sante Et Of La Recherche Medicale Umr S 1124 | Jaubert A..-M.,Institute National Of La Sante Et Of La Recherche Medicale Umr S 1124 | Jaubert A..-M.,University of Versailles | And 14 more authors.
Molecular Nutrition and Food Research | Year: 2014

Scope: During aging, increased visceral adipose tissue (AT) mass may result in impaired metabolic status. A citrulline (CIT)-supplemented diet reduces AT mass in old rats. We hypothesized that CIT could directly affect fatty acid (FA) metabolism in retroperitoneal AT. Methods and results: A 24-h exposure of AT explants from old (25 months) rats to 2.5 mM CIT induced a 50% rise in glycerol and FA release, which was not observed in explants from young (2 months) animals. The phosphorylated form of hormone-sensitive lipase, a key lipolytic enzyme, was 1.5-fold higher in CIT-treated explants from old and young rats, whereas glyceroneogenesis, that provides glycerol-3P requested for FA re-esterification, and its key enzyme phosphoenolpyruvate carboxykinase, were down-regulated 40-70%. Specifically in young rats, beta-oxidation capacity and gene expressions of carnitine palmitoyl transferase 1-b and very long chain acyl-CoA dehydrogenase were strongly up-regulated by CIT. In contrast, in old rats, while glyceroneogenesis was lower, beta-oxidation was not affected, enabling increased FA release. Conclusion: Hence, in visceral AT, CIT exerts a specific induction of the beta-oxidation capacity in young rats and a selective stimulation of FA release in old rats, therefore providing a direct mechanism of CIT action to reduce AT mass. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Joffin N.,University of Paris Descartes | Joffin N.,Institute National Of La Sante Et Of La Recherche Medicale Umr S 1124 | Jaubert A..-M.,Institute National Of La Sante Et Of La Recherche Medicale Umr S 1124 | Jaubert A..-M.,University of Versailles | And 16 more authors.
Molecular Nutrition and Food Research | Year: 2014

Scope: High-fat diet (HFD) increases visceral adipose tissue (AT). Our aim was to evaluate whether citrulline (CIT) affected nonesterified fatty acid (NEFA) metabolism in AT from HFD-fed rats. Methods and results: Rats were fed for 8 weeks with either a control diet (CD) or HFD. Retroperitoneal AT explants were exposed to 2.5 mmol/L CIT for 24 h. We analyzed lipolysis, beta-oxidation, glyceroneogenesis, and the expression of the key associated enzymes. CIT doubled NEFA release selectively in HFD AT. Phosphorylation of hormone-sensitive lipase was upregulated 50 and 100% by CIT in CD and HFD AT, respectively. Under CIT, beta-oxidation increased similarly whatever the diet, whereas glyceroneogenesis, which permits NEFA re-esterification, was downregulated 50 and 80% in CD and HFD AT, respectively. In the latter, the important decrease in re-esterification probably explains the rise of NEFA release. A pretreatment with the nitric oxide synthase inhibitor N ω-nitro-l-arginine methyl ester abolished CIT effects. Conclusion: These results demonstrate direct lipolytic and antiglyceroneogenic effects of CIT on CD and HFD AT. The selective CIT-mediated NEFA release from HFD AT was probably the consequence of the drastic decrease in glyceroneogenesis and nitric oxide was a mediator of CIT effects. These results provide evidence for a direct action of CIT on AT to reduce overweight. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Magerus-Chatinet A.,French Institute of Health and Medical Research | Magerus-Chatinet A.,University of Paris Descartes | Stolzenberg M.-C.,French Institute of Health and Medical Research | Stolzenberg M.-C.,University of Paris Descartes | And 18 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013

Background: Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphoproliferation, accumulation of double-negative T cells, hypergammaglobulinemia G and A, and autoimmune cytopenia. Objectives: Although mostly associated with FAS mutations, different genetic defects leading to impaired apoptosis have been described in patients with ALPS, including the FAS ligand gene (FASLG) in rare cases. Here we report on the first case of complete FAS ligand deficiency caused by a homozygous null mutant. Methods: Double-negative T-cell counts and plasma IL-10 and FAS ligand concentrations were determined as ALPS markers. The FASLG gene was sequenced, and its expression was analyzed by means of Western blotting. FAS ligand function was assessed based on reactivation-induced cell death. Results: We describe a patient born to consanguineous parents who presented with a severe form of ALPS caused by FASLG deficiency. Although the clinical presentation was compatible with a homozygous FAS mutation, FAS-induced apoptosis was normal, and plasma FAS ligand levels were not detectable. This patient carries a homozygous, germline, single-base-pair deletion in FASLG exon 1, leading to a premature stop codon (F87fs x95) and a complete defect in FASLG expression. The healthy parents were each heterozygous for the mutation, confirming its recessive trait. Conclusion: FAS ligand deficiency should be screened in patients presenting with ALPS features but lacking the usual markers, including plasma soluble FAS ligand and an in vitro apoptotic defect. An activation-induced cell death test could help in discrimination. © 2012 American Academy of Allergy, Asthma & Immunology.

Breuillard C.,Laboratoire Of Biologie Of La Nutrition | Darquy S.,Laboratoire Of Biologie Of La Nutrition | Curis E.,University of Paris Descartes | Neveux N.,Laboratoire Of Biologie Of La Nutrition | And 3 more authors.
Critical Care Medicine | Year: 2012

OBJECTIVE: Obese and type 2 diabetic patients present metabolic disturbance-related alterations in nonspecific immunity, to which the decrease in their plasma arginine contributes. Although diabetes-specific formulas have been developed, they have never been tested in the context of an acute infectious situation as can be seen in intensive care unit patients. Our aim was to investigate the effects of a diabetes-specific diet enriched or not with arginine in a model of infectious stress in a diabetes and obesity situation. As a large intake of arginine may be deleterious, this amino acid was given in graded fashion. DESIGN: Randomized, controlled experimental study. SETTING: University research laboratory. SUBJECTS: Zucker diabetic fatty rats. INTERVENTIONS: Gastrostomized Zucker diabetic fatty rats were submitted to intraperitoneal lipopolysaccharide administration and fed for 7 days with either a diabetes-specific enteral nutrition without (G group, n = 7) or with graded arginine supply (1-5 g/kg/day) (GA group, n = 7) or a standard enteral nutrition (HP group, n = 10). MEASUREMENTS AND MAIN RESULTS: Survival rate was better in G and GA groups than in the HP group. On day 7, plasma insulin to glucose ratio tended to be lower in the same G and GA groups. Macrophage tumor necrosis factor-α (G: 5.0 ± 1.1 ng/2 × 10 cells•hr; GA: 3.7 ± 0.8 ng/2 × 10 cells•hr; and HP: 1.7 ± 0.6 ng/2 × 10 cells•hr; p < .05 G vs. HP) and nitric oxide (G: 4.5 ± 1.1 ng/2 × 10 cells•hr; GA: 5.1 ± 1.0 ng/2 × 10 cells•hr; and HP: 1.0 ± 0.5 nmol/2 × 10 cells•hr; p < .05 G and GA vs. HP) productions were higher in the G and GA groups compared to the HP group. Macrophages from the G and GA groups exhibited increased arginine consumption. CONCLUSIONS: In diabetic obese and endotoxemic rats, a diabetes-specific formula leads to a lower mortality, a decreased insulin resistance, and an improvement in peritoneal macrophage function. Arginine supplementation has no additional effect. These data support the use of such disease-specific diets in critically ill diabetic and obese patients. Copyright © 2012 by the Society of Critical Care.

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