Topiramate stimulates glucose transport through AMP-activated protein kinase-mediated pathway in L6 skeletal muscle cells.
The use of topiramate (TPM) in the treatment of binge-eating disorder, bulimia nervosa, and antipsychotic-induced weight gain has recently increased, however, the exact molecular basis for its effects on body weight reduction and improved glucose homeostasis, is yet to be elucidated. Here we investigated the effect and signaling pathway of TPM on glucose uptake in L6 rat skeletal muscle cells, which account for >70% of glucose disposal in the body. Intriguingly, we found that TPM (10 microM) stimulated the rate of glucose uptake up to twofold increase. And TPM-stimulated glucose transport was inhibited with the overexpression of dominant-negative form of AMP-activated protein kinase (AMPK), an important mediator in glucose transport, implicating that AMPK-mediated pathway is involved. The TPM-stimulated glucose transport was blocked by SB203580, a specific inhibitor of AMPK downstream mediator, p38 mitogen-activated protein kinase (MAPK) protein. LY294002, an inhibitor of phosphatidylinositol (PI) 3-kinase, which is another crucial mediator in independent glucose transport pathway, did not inhibit TPM-stimulated glucose transport. We also found that TPM increased the phosphorylation level of AMPK and p38 MAPK, whereas no effect on the activity of PI 3-kinase of TPM, when assessed by PI 3-kinase assay, was observed. These results together suggest that TPM stimulates glucose transport, not via PI 3-kinase mediated, but via AMPK-mediated pathway in skeletal muscle cells, thereby contributing to the body weight regulation and glucose homeostasis.
Ha
E
E
Department of Biochemistry, College of Medicine, Kyung Hee University, Seoul, Republic of Korea.
Yim
S V
SV
Jung
K H
KH
Yoon
S H
SH
Zheng
L T
LT
Kim
M J
MJ
Hong
S J
SJ
Choe
B K
BK
Baik
H H
HH
Chung
J H
JH
Kim
J W
JW
D055372:AMP-Activated Protein Kinases; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001692:Biological Transport; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007093:Imidazoles / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D000077236:Topiramate; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D019440:Anti-Obesity Agents; D007093:Imidazoles; D009097:Multienzyme Complexes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000077236:Topiramate; D005632:Fructose; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C093642:SB 203580