RESUMEN
Leptin is an adipokine that regulates adipose tissue mass through membrane-anchored leptin receptor (Ob-R). Extracellular domain of Ob-R in plasma is called soluble leptin receptor (sOb-R), and is the main leptin-binding protein. Based on a previous DNA microarray analysis that showed induction of hepatic Ob-R mRNA in low-protein diet-fed mice, this study aimed to clarify the effect of dietary protein restriction on hepatic Ob-R mRNA and plasma sOb-R levels. First, the effect of protein restriction on hepatic Ob-R mRNA level was examined together with fasting and food restriction using male rats as common experimental model for nutritional research. Hepatic Ob-R mRNA level was increased by feeding low-protein diet for 7 d, although not significantly influenced by 12-h fasting and sixty percent restriction in food consumption. Then, effect of protein restriction on liver Ob-R and plasma sOb-R was investigated using male mice because specific sOb-R ELISA was more available for mice. Hepatic Ob-R mRNA level was also increased in protein restricted-mice although it did not increase in hypothalamus. Hepatic Ob-R protein was decreased, whereas plasma sOb-R was increased by protein restriction. Because the concentration of sOb-R increased without changing plasma leptin concentration, free leptin in plasma was significantly reduced. The direct effect of amino acid deprivation on Ob-R mRNA level was not observed in rat hepatoma cells H4IIE cultured in amino acid deprived medium. In conclusion, dietary protein restriction increased hepatic Ob-R mRNA, resulting in increased plasma sOb-R concentration, which in turn, reduces plasma free leptin level and may modulate leptin activity.
Asunto(s)
Dieta con Restricción de Proteínas , Proteínas en la Dieta , Hígado/metabolismo , Receptores de Leptina/sangre , Receptores de Leptina/metabolismo , Tejido Adiposo/metabolismo , Alimentación Animal , Animales , Línea Celular Tumoral , Femenino , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
BACKGROUND: Classical galactosemia is caused by severe galactose-1-phosphate uridyltransferase deficiency. Despite life-long galactose-restriction, many patients experience long-term complications. Intoxication by galactose and its metabolites as well as over-restriction of galactose may contribute to the pathophysiology. We provided temporary low-dose galactose supplements to patients. We assessed tolerance and potential beneficial effects with clinical monitoring and measurement of biochemical, endocrine, and IgG N-glycosylation profiles. METHODS: We enrolled 26 patients (8.6 ± 1.9 y). Thirteen were provided with 300 mg of galactose/day followed by 500 mg for 2 wk each (13 patient controls). RESULTS: We observed no clinical changes with the intervention. Temporary mild increase in galactose-1-phosphate occurred, but renal, liver, and bone biochemistry remained normal. Patients in the supplementation group had slightly higher leptin levels at the end of the study than controls. We identified six individuals as "responders" with an improved glycosylation pattern (decreased G0/G2 ratio, P < 0.05). There was a negative relationship between G0/G2 ratio and leptin receptor sOb-R in the supplementation group (P < 0.05). CONCLUSION: Temporary low-dose galactose supplementation in children over 5 y is well tolerated in the clinical setting. It leads to changes in glycosylation in "responders". We consider IgG N-glycan monitoring to be useful for determining individual optimum galactose intake.
Asunto(s)
Suplementos Dietéticos , Galactosa/administración & dosificación , Galactosemias/tratamiento farmacológico , Huesos/patología , Niño , Preescolar , Estudios de Cohortes , Sistema Endocrino , Femenino , Galactosa/uso terapéutico , Glicosilación , Células HEK293 , Homocigoto , Humanos , Inmunoglobulina G/inmunología , Riñón/patología , Lactosa/química , Leptina/sangre , Hígado/patología , Masculino , Mutación , Proyectos Piloto , Receptores de Leptina/sangre , Transducción de SeñalRESUMEN
OBJECTIVE: To investigate the effect of reducing the n-6/n-3 fatty acid ratio in maternal nutrition on the maternal and cord blood leptin axis and their association with infant body composition up to 2 years. DESIGN AND METHODS: 208 healthy pregnant women were randomized to either a dietary intervention to reduce the n-6/n-3 fatty acid ratio from 15th week of gestation until 4 months postpartum or a control group. Leptin, soluble leptin receptor and free leptin index were determined in maternal and cord plasma and related to infant body composition assessed by skinfold thicknesses up to 2 years. RESULTS: The intervention had no effect on either the maternal or fetal leptin axis. Maternal leptin in late pregnancy was inversely related to infant weight and lean body mass (LBM) up to 2 years, after multiple adjustments. Cord leptin was positively related to weight, body fat, and LBM at birth, and inversely associated with weight, BMI, fat mass, and LBM at 2 years and weight gain up to 2 years. The contribution of cord leptin to infant outcomes was overall stronger compared with maternal leptin. CONCLUSIONS: Both, maternal and fetal leptin were associated with subsequent infant anthropometry with a greater impact of fetal leptin.
Asunto(s)
Composición Corporal , Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-6/sangre , Feto/química , Leptina/sangre , Fenómenos Fisiologicos Nutricionales Maternos , Tejido Adiposo/metabolismo , Antropometría , Índice de Masa Corporal , Peso Corporal , Preescolar , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-6/administración & dosificación , Conducta Alimentaria , Femenino , Sangre Fetal/química , Humanos , Lactante , Lactancia , Modelos Lineales , Embarazo , Receptores de Leptina/sangre , Grosor de los Pliegues CutáneosRESUMEN
To determine how astrocytic leptin signaling regulates the physiological response of mice to diet-induced obesity (DIO), we performed metabolic analyses and hypothalamic leptin signaling assays on astrocytic leptin-receptor knockout (ALKO) mice in which astrocytes lack functional leptin receptor (ObR) signaling. ALKO mice and wild-type (WT) littermate controls were studied at different stages of DIO with measurement of body wt, percent fat, metabolic activity, and biochemical parameters. When fed regular chow, the ALKO mice had similar body wt, percent fat, food intake, heat dissipation, respiratory exchange ratio, and activity as their WT littermates. There was no change in blood concentrations of triglyceride, soluble leptin receptor (sObR), mRNA for leptin and uncoupling protein 1 (UCP1) in adipose tissue, and insulin sensitivity. Unexpectedly, in response to a high-fat diet the ALKO mice had attenuated hyperleptinemia and sObR, a lower level of leptin mRNA in subcutaneous fat, and a paradoxical increase in UCP1 mRNA. Thus, ALKO mice did not show the worsening of obesity that occurs with normal WT mice and the neuronal ObR mutation that results in morbid obesity. The findings are consistent with a competing, counterregulatory model between neuronal and astrocytic leptin signaling.
Asunto(s)
Astrocitos/metabolismo , Dieta Alta en Grasa , Hipotálamo/metabolismo , Leptina/metabolismo , Obesidad/prevención & control , Receptores de Leptina/deficiencia , Adiposidad , Animales , Biomarcadores/sangre , Glucemia/metabolismo , Peso Corporal , Modelos Animales de Enfermedad , Metabolismo Energético , Genotipo , Insulina/sangre , Canales Iónicos/genética , Canales Iónicos/metabolismo , Leptina/sangre , Leptina/genética , Ratones , Ratones Noqueados , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Actividad Motora , Obesidad/sangre , Obesidad/genética , Fenotipo , ARN Mensajero/sangre , Receptores de Leptina/sangre , Receptores de Leptina/genética , Transducción de Señal , Grasa Subcutánea/metabolismo , Factores de Tiempo , Triglicéridos/sangre , Proteína Desacopladora 1RESUMEN
Metformin demonstrates anorectic effects in vivo and inhibits neuropeptide Y expression in cultured hypothalamic neurons. Here we investigated the mechanisms implicated in the modulation of feeding by metformin in animals rendered obese by long-term high-fat diet (diet-induced obesity [DIO]) and in animals resistant to obesity (diet resistant [DR]). Male Long-Evans rats were kept on normal chow feeding (controls) or on high-fat diet (DIO, DR) for 6 months. Afterward, rats were treated 14 days with metformin (75 mg/kg) or isotonic sodium chloride solution and killed. Energy efficiency, metabolic parameters, and gene expression were analyzed at the end of the high-fat diet period and after 14 days of metformin treatment. At the end of the high-fat diet period, despite higher leptin levels, DIO rats had higher levels of hypothalamic neuropeptide Y expression than DR or control rats, suggesting a central leptin resistance. In DIO but also in DR rats, metformin treatment induced significant reductions of food intake accompanied by decreases in body weight. Interestingly, the weight loss achieved by metformin was correlated with pretreatment plasma leptin levels. This effect was paralleled by a stimulation of the expression of the leptin receptor gene (ObRb) in the arcuate nucleus. These data identify the hypothalamic ObRb as a gene modulated after metformin treatment and suggest that the anorectic effects of the drug are potentially mediated via an increase in the central sensitivity to leptin. Thus, they provide a rationale for novel therapeutic approaches associating leptin and metformin in the treatment of obesity.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Hipoglucemiantes/farmacología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Metformina/farmacología , Obesidad/metabolismo , Receptores de Leptina/sangre , Proteína Relacionada con Agouti/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal/fisiología , Humanos , Insulina/sangre , Leptina/sangre , Masculino , Neuropéptido Y/metabolismo , Proopiomelanocortina/metabolismo , ARN/química , ARN/genética , Distribución Aleatoria , Ratas , Ratas Long-Evans , Receptores de Leptina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estadísticas no ParamétricasRESUMEN
BACKGROUND: Obesity seems to be linked to the hypothalamic involvement in craniopharyngioma. We evaluated the pre-surgery relationship between the degree of this involvement on magnetic resonance imaging and insulin resistance, as evaluated by the homeostasis model insulin resistance index (HOMA). As insulin-like growth factor 1, leptin, soluble leptin receptor (sOB-R) and ghrelin may also be involved, we compared their plasma concentrations and their link to weight change. METHODS: 27 children with craniopharyngioma were classified as either grade 0 (n = 7, no hypothalamic involvement), grade 1 (n = 8, compression without involvement), or grade 2 (n = 12, severe involvement). RESULTS: Despite having similar body mass indexes (BMI), the grade 2 patients had higher glucose, insulin and HOMA before surgery than the grade 0 (P = 0.02, <0.05 and 0.02 respectively) and 1 patients (P < 0.02 and <0.03 for both insulin and HOMA). The grade 0 (5.8 +/- 4.9) and 1 (7.2 +/- 5.3) patients gained significantly less weight (kg) during the year after surgery than did the grade 2 (16.3 +/- 7.4) patients. The pre-surgery HOMA was positively correlated with these weight changes (P < 0.03). The data for the whole population before and 6-18 months after surgery showed increases in BMI (P < 0.0001), insulin (P < 0.005), and leptin (P = 0.0005), and decreases in sOB-R (P < 0.04) and ghrelin (P < 0.03). CONCLUSION: The hypothalamic involvement by the craniopharyngioma before surgery seems to determine the degree of insulin resistance, regardless of the BMI. The pre-surgery HOMA values were correlated with the post-surgery weight gain. This suggests that obesity should be prevented by reducing inn secretion in those cases with hypothalamic involvement.
Asunto(s)
Craneofaringioma/patología , Hipotálamo/patología , Resistencia a la Insulina , Obesidad/etiología , Neoplasias Hipofisarias/patología , Adolescente , Glucemia/análisis , Niño , Preescolar , Craneofaringioma/complicaciones , Craneofaringioma/metabolismo , Craneofaringioma/cirugía , Femenino , Ghrelina/sangre , Homeostasis , Terapia de Reemplazo de Hormonas , Humanos , Hidrocortisona/sangre , Hipofisectomía , Hipopituitarismo/tratamiento farmacológico , Hipopituitarismo/etiología , Hipotálamo/fisiopatología , Factor I del Crecimiento Similar a la Insulina/análisis , Leptina/sangre , Masculino , Modelos Biológicos , Obesidad/sangre , Obesidad/fisiopatología , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/cirugía , Receptores de Leptina/sangre , Estudios Retrospectivos , Método Simple Ciego , Tiroxina/sangre , Aumento de PesoRESUMEN
OBJECTIVE: To investigate the mechanism underlying the protective effects of a traditional Chinese medicinal formula, Baoganning, against liver fibrosis. METHODS: Male Wistar rats were subjected to injection of carbon tetrachloride- peanut oil mixture and given daily 5% alcoholic beverage, and 2 days after the injection, Baoganning was administered intragastrically at two different doses for 6 weeks. Radioimmunoassay was used to detect serum leptin level, and immunohistochemistry employed to examine the effect of Baoganning on expressions of leptin and its receptor in the liver tissue of the rats. RESULTS: Compared with the normal control group, the rats in the liver fibrosis model group and Baoganning-treated groups showed significantly increased serum leptin levels (P<0.01), and the serum leptin level was significantly lower in Baoganning group than in the liver fibrosis model group (P<0.01). Baoganning significantly reduced the hepatic expression of leptin and OB-Rb in rats with liver fibrosis in comparison with their expression in the model group (P<0.01). CONCLUSION: Baoganning can effectively ameliorate liver fibrosis in rats possibly through reducing serum leptin level and inhibiting hepatic leptin and its receptor expressions.