Metformin restores leptin sensitivity in high-fat-fed obese rats with leptin resistance.
To evaluate whether metformin enhances leptin sensitivity, we measured leptin sensitivity after 4 weeks of metformin treatment (300 mg/kg daily) in both standard chow and high-fat-fed obese rats. Anorexic and fat-losing responses after intracerebroventricular leptin infusion for 7 days (15 microg daily per rat) in standard chow rats were enhanced by metformin treatment, and these responses to leptin were attenuated in high-fat-fed obese rats compared with age-matched standard chow rats. However, these responses to leptin were corrected by metformin treatment in high-fat-fed obese rats. Moreover, serum concentrations of leptin and insulin were decreased dramatically by leptin in metformin-treated standard chow and high-fat-fed obese rats. The hypothalamic phosphorylated AMP-activated protein kinase level was decreased by lower leptin dose in metformin-treated rats than in untreated rats. In an acute study, metformin treatment also increased the anorexic effect of leptin (5 microg), and this was accompanied by an increased level of phosphorylated signal transducer and activator of transcription 3 in the hypothalamus. These results suggest that metformin enhances leptin sensitivity and corrects leptin resistance in high-fat-fed obese rats and that a combination therapy including metformin and leptin would be helpful in the treatment of obesity.
Kim
Yong-Woon
YW
Department of Physiology, College of Medicine, Yeungnam University, #317-1, Daemyungdong, Namgu, Daegu 705-717, Republic of Korea. ywkim@med.yu.ac.kr
Kim
Jong-Yeon
JY
Park
Yong-Hoon
YH
Park
So-Young
SY
Won
Kyu-Chang
KC
Choi
Kwang-Hae
KH
Huh
Jung-Yoon
JY
Moon
Ki-Hak
KH
D055372:AMP-Activated Protein Kinases; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007031:Hypothalamus / Q000737:chemistry; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D009097:Multienzyme Complexes / Q000032:analysis; D009765:Obesity / Q000188:drug therapy*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology
D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D020738:Leptin; D009097:Multienzyme Complexes; D050796:STAT3 Transcription Factor; D011333:Pro-Opiomelanocortin; D003346:Corticotropin-Releasing Hormone; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases