Topiramate stimulates glucose transport through AMP-activated protein kinase-mediated pathway in L6 skeletal muscle cells

Abstract

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 470% of glucose disposal in the body. Intriguingly, we found that TPM (10 mM) 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 TPMstimulated 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.

Ganoderma lucidum extract stimulates glucose uptake in L6 rat skeletal muscle cells.

“…3A). Ha et al (2006) reported that topiramate stimulated the rate of glucose transport in L6 skeletal muscle cells. From these results, we suggest that G. lucidum extract also increases glucose uptake by stimulating AMPK activity in skeletal muscle cells.…”

The insulin sensitizing effect of topiramate involves KATP channel activation in the central nervous system

“…Furthermore, both basal or insulin‐stimulated glucose uptake and insulin signalling in insulin‐sensitive or insulin‐resistant cultured muscle cells (differentiated C2C12 myotubes) were not affected by topiramate. Our data are in contrast to a previous study that reported that topiramate increases glucose uptake in cultured insulin‐sensitive L6 cells, a rat skeletal muscle cell line, via an AMPK‐mediated pathway (Ha et al ., ). The phosphorylation level of AMPK (Thr172) was not increased when we treated C2C12 myotubes with topiramate (data not shown).…”

Gender‐related issues in the pharmacology of new anti‐obesity drugs

“…The weight‐lowering mechanism of topiramate remains uncertain, but seems to involve both central and peripheral targets. Topiramate acts peripherally by enhancing insulin sensitivity and activating AMP‐kinase (AMPK) and acetyl‐CoA carboxylase in skeletal muscles, whereas its central effect is mainly exerted in the hypothalamus where it potentiates both leptin‐induced Jak‐Stat and MAPK/ERK and insulin‐induced insulin receptor substrate/Akt/forkhead box O1 pathway activation . These effects on leptin and insulin signalling ultimately lead to an increase in the transcription of genes encoding for anorectic peptides including POMC, thyrotropin‐releasing hormone (TRH), and corticotropin‐releasing hormone (CRH) .…”