The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats.
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.
The Department of General Medicine, Affiliated Hospital of Qingdao Medical University, Qingdao, China.
Wen-Shan
WS
Lv
Jun-Ping
JP
Wen
Li
L
Li
Rui-Xia
RX
Sun
Jing
J
Wang
Yu-Xin
YX
Xian
Cai-Xia
CX
Cao
Yun-Long
YL
Wang
Yan-Yan
YY
Gao
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002853:Chromatography, Liquid; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053719:Tandem Mass Spectrometry
C515197:AGRP protein, rat; D054369:Agouti-Related Protein; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D009478:Neuropeptide Y; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D011333:Pro-Opiomelanocortin; D008687:Metformin; D055372:AMP-Activated Protein Kinases