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.