Melatonin ameliorates high fat diet-induced diabetes and stimulates glycogen synthesis via a PKCzeta-Akt-GSK3beta pathway in hepatic cells.
Low levels of melatonin in circulation had been reported to be related to the development of diabetes. Melatonin administration in animals increases hepatic glycogen content to lower blood glucose. However, the signaling pathway for these effects is still unclear. The present study shows that intraperitoneal injection of 10 mg/kg melatonin ameliorated glucose utilization and insulin sensitivity in high fat diet-induced diabetic mice with an increase in hepatic glycogen and improvement in liver steatosis. We used HepG2 cells to investigate the signaling pathways for the melatonin-stimulated hepatic glycogen increment. Treatment of HepG2 cells with 1 nm melatonin markedly increased glycogen synthesis which was blocked by the melatonin receptor antagonist luzindole. In addition, melatonin increased the phosphorylation of subcellular signals at the level of protein kinase C zeta (PKCzeta), Akt, and glycogen synthase kinase 3beta (GSK3beta) while the increase in glycogen synthesis induced by melatonin was inhibited by PKCzeta pseudo-peptide. However, 3',5'-cyclic adenosine monophosphate-activated protein kinase (AMPK) was not influenced by melatonin treatment. Taken together, melatonin improves glucose intolerance and insulin resistance in high fat diet-induced diabetic mice and stimulates glycogen synthesis via a PKCzeta-Akt-GSK3beta pathway in HepG2 cells.
Shieh
Jiunn-Min
JM
Department of Chest Medicine, Chi-Mei Medical Center, Yong Kang City, Taiwan.
Wu
Hung-Tsung
HT
Cheng
Kai-Chun
KC
Cheng
Juei-Tang
JT
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003921:Diabetes Mellitus, Experimental / Q000209:etiology*; D004041:Dietary Fats / Q000009:adverse effects*; D005234:Fatty Liver / Q000188:drug therapy; D006003:Glycogen / Q000096:biosynthesis* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000099221:Protein Kinase C zeta
D000975:Antioxidants; D004041:Dietary Fats; D006003:Glycogen; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D008550:Melatonin; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D000099221:Protein Kinase C zeta; C000605507:Gsk3b protein, mouse