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Recent studies have revealed the role of L-citrulline (L-CIT) in thermoregulation, but very little is known about the mechanisms involved. In this study, nitric oxide synthase inhibition and endotoxin-induced fever were used to investigate the effects of L-CIT on body temperature and inflammatory responses. In experiment 1, NW-nitro-L-arginine methyl ester (L-NAME, 150 mg/kg BW), was i. p. injected into chicks fed with basal (CON) or L-CIT diets for 14 days. In experiment 2, Lipopolysaccharide (LPS, 2 mg/kg BW) was i. p. injected following 21d feeding with CON or L-CIT diets. In experiment 3, chickens were injected with either L-NAME, LPS, or L-NAMEþLPS following 26 days feeding with CON or L-CIT diets. The rectal (RT), ear (ET), and core body temperature (CBT) of chickens were examined. Results showed that L-NAME effectively decreased the RT, ET, CBT, and plasma NO concentration. In contrast, LPS increased NO levels and initiated hyperthermia by increasing RT, ET, CBT, and PGE2 levels. L-CIT diet reduced the mean CBT in experiment 1 and diminished the NO level, PGE2 level, and mean RT in experiment 3. Co-administration of L-CITþLPS upregulated IL-6 expression, whereas, LPS injection alone induced IL-10, IL-1b, and TLR4 gene expressions. Therefore, this study reveals that L-CIT-induced hypothermia was related to NO inhibition and a decrease in PGE2 concentration. Conversely, LPS induced hyperthermia was associated with an increase in both NO and PGE2 concentrations. [ABSTRACT FROM AUTHOR]

The mechanism that mediates L-citrulline (L-Cit) hypothermia is poorly understood, and the involvement of nitric oxide signaling has not been fully elucidated. Therefore, this study aimed to determine L-Cit's influence on body temperature and to ascertain the central and peripheral mechanisms associated with this response. Chicks responded to intracerebroventricular (ICV) injection of L-Cit with high and low body temperatures (P < 0.05) depending on the dose tested, for both the surface and rectal temperatures. Peripheral (i.p.) L-Cit injection did not affect body temperature responses. Nitric oxide (NO) concentration and NO synthase (NOS) were influenced with varying doses of L-Cit. Hypothalamic NO was increased at 4 µg L-Cit whereas, plasma iNOS was elevated at 2µg L-Cit treatment. However, i.p. L-Cit did not change the NO content, rather it induced higher (P < 0.05) plasma tNOS and iNOS activity, and further upregulated iNOS and nNOS gene expression in the hypothalamus. In addition, ICV L-Cit potentiated a pro- versus anti-inflammatory milieu with the induction of IL-8, IL-10, and TGFβ (P < 0.05), which may be related to the changes in body temperature. Following ICV L-Cit administration, it was observed that L-Cit caused dose variable changes in the ultrastructure of hypothalamic neurons. The lowest dose was associated with a higher number of dead or degenerating neurons, whereas the highest L-Cit dose had fewer neuronal numbers with larger sizes. Therefore, this study shows that central and peripheral L-Cit administration imposes changes in body temperature, nitric oxide production, and inflammatory responses, in a dose-dependent manner. [ABSTRACT FROM AUTHOR]