RESUMEN
L-Citrulline (L-Cit), a free amino acid from watermelon, has effects on hypertension and anti-oxidization; however, there are few reports of effects related to obesity. This study investigated the effects and mechanism of L-Cit on anti-obesity in obese/diabetic KK-Ay mice and high-fat diet fed Sprague-Dawley (SD) rats. L-Cit induced significant reduction of food intake, body weight and fat tissue mass in obese/diabetic KK-Ay mice. Moreover, blood glucose level did not change but free fatty acid level and serum insulin level were significantly decreased by treatment with L-Cit, suggesting that L-Cit improved glucose and fatty metabolism in obesity model mice. As well as obese/diabetic KK-Ay mice, there was a significant decrease in food intake and a tendency of body weight to decrease in high-fat diet fed SD rats treated with L-Cit. Also, levels of proopiomelanocortin (POMC), a food intake suppression peptide, increased in the hypothalamus. Our study suggests that L-Cit improves metabolic syndrome through decreased body weight by appetite suppression.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Depresores del Apetito/uso terapéutico , Citrulina/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Obesidad/tratamiento farmacológico , Animales , Fármacos Antiobesidad/farmacología , Depresores del Apetito/farmacología , Citrulina/farmacología , Diabetes Mellitus Experimental/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ratones , Obesidad/inducido químicamente , Obesidad/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Insulin resistance is characterized by deficient responses to insulin in its target tissues. In the present study, we examined the effects of L-Citrulline (L-Cit) on insulin sensitivity and signaling cascades in rat hepatoma H4IIE cells and SHRSP.Z-Leprfa/IzmDmcr rats. METHODS: H4IIE cells were pretreated in the presence or absence of 250 µM L-Cit in serum-free medium and then incubated in the presence or absence of 0.1 nM insulin. Rats were allocated into 2 groups; a control group (not treated) and L-Cit group (2 g/kg/day, L-Cit) and treated for 8 weeks. RESULTS: L-Cit enhanced the insulin-induced phosphorylation of Akt in H4IIE cells. Moreover, the inhibited expression of Dex/cAMP-induced PEPCK mRNA by insulin was enhanced by the L-Cit treatment. The phosphorylation of tyrosine, which is upstream of Akt, in insulin receptor substrate-1 (IRS-1) was increased by the L-Cit treatment. The L-Cit-induced enhancement in insulin signaling was not related to the binding affinity of insulin to the insulin receptor or to the expression of the insulin receptor, but to a decrease in the phosphorylation of serine 1101 in IRS-1. These results were also confirmed in animal experiments. In the livers of L-Cit-treated rats, PI3K/Akt signaling was improved by decreases in the phosphorylation of serine 1101. CONCLUSIONS: We herein demonstrated for the first time the beneficial effects of L-Cit on improved insulin resistance associated with enhanced insulin sensitivity. These results may have clinical applications for insulin resistance and the treatment of type-2 diabetes.