RESUMEN
Metformin appears to be involved in altering energy expenditure and thermogenesis, and could affect hypothalamic feeding circuits. However, it is not clear whether metformin is able to cross the blood-brain barrier (BBB) to reach the hypothalamus and exert a direct effect on the central nervous system. Here we show the presence of metformin in cerebrospinal fluid (CSF) of diabetic rats administered orally with metformin which was confirmed by detecting the concentration of metformin with liquid chromatography-tandem mass spectrometry. Food intake of diabetic rats treated with metformin was reduced, and glucose homeostasis was gained. Expression of orexigenic peptides neuropeptide Y (NPY) and agouti-related protein (AgRP) decreased in the hypothalamus of metformin-treated diabetic rats, though anorexigenic peptides pro-opiomelanocortin (POMC) did not change significantly. The phosphorylation of signal transducer and activator of transcription 3 (STAT3) was increased but phosphorylated AMP-activated kinase (AMPK) was similar in the hypothalamus of metformin-treated diabetic rats. Our findings suggest that metformin may cross BBB and play a central mechanism on regulation of food intake in the hypothalamus. The anorexic effect of metformin may be mediated by inhibition of NPY and AgRP gene expression through the STAT3 signaling pathway.
Asunto(s)
Diabetes Mellitus Experimental , Ingestión de Alimentos/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipoglucemiantes/administración & dosificación , Hipotálamo/efectos de los fármacos , Metformina/administración & dosificación , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Administración Oral , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Animales , Glucemia/efectos de los fármacos , Cromatografía Liquida , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Modelos Animales de Enfermedad , Hipoglucemiantes/sangre , Hipoglucemiantes/líquido cefalorraquídeo , Hipotálamo/metabolismo , Masculino , Metformina/sangre , Metformina/líquido cefalorraquídeo , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Fosforilación/efectos de los fármacos , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Espectrometría de Masas en TándemRESUMEN
Recently, it has been reported that metformin may attenuate inflammation and directly act on the central nervous system. Using the HPLC method, in Wistar rats, we assessed the changes in metformin concentrations in various brain regions (pituitary gland, olfactory bulb, hypothalamus, cerebellum, hippocampus, striatum, frontal cortex), cerebrospinal fluid and plasma after single and chronic oral administration, in the model of systemic inflammation induced by lipopolysaccharide (ip). Regarding the influence of systemic inflammation on metformin distribution, the pituitary gland demonstrated the highest its level after single and chronic administration (28.8 ± 3.5 nmol/g and 24.9 ± 3.2 nmol/g, respectively). We concluded that orally-dosed metformin rapidly crosses the blood-brain barrier and differently accumulates in structures of the central nervous system.
