BMS309403 Stimulates Glucose Uptake in Myotubes through Activation of AMP-Activated Protein Kinase

Wanhua Lin,Jia Li,Lina Zhang,Dongye Wang,Xiaoli Huang,Shouguang Jin,Xiujie Liu,Donghai Wu,Ke Ding,Qilong Peng,Jingya Li,Dongmei Chen,Kuai Li,Lei Xu,Aimin Xu

doi:10.1371/journal.pone.0044570

Abstract

BMS309403 is a biphenyl azole inhibitor against fatty acid binding protein 4 (FABP4) and regarded as a lead compound for effective treatment of obesity related cardio-metabolic diseases. Here we discovered an off-target activity of BMS309403 in that it stimulates glucose uptake in C2C12 myotubes in a temporal and dose dependent manner via activation of AMP-activated protein kinase (AMPK) signaling pathway but independent of FABPs. Further analysis indicated that BMS309403 activates AMPK through increasing the ratio of intracellular AMP:ATP while decreasing mitochondrial membrane potential. These findings provide mechanistic insights on the action of BMS309403.

Highlights

BMS309403 is a biphenyl azole inhibitor designed to target fatty acid binding protein 4 (FABP4) with a Ki value less than 2 nM [1]
FABP4 is predominantly present in macrophages and adipocytes, its expression has been detected in other tissues such as endothelial cells [3] and human muscles [4]
We found that BMS309403 increased glucose uptake in C2C12 myotubes in a time-dependent manner (Fig. 1A)

Summary

Introduction

BMS309403 is a biphenyl azole inhibitor designed to target FABP4 with a Ki value less than 2 nM [1]. BMS309403 inhibits lipid accumulation, cholesterol efflux and inflammatory responses in macrophages, and suppresses fatty acid uptake in adipocytes, in a FABP4-dependent manner [2]. FABP4 is predominantly present in macrophages and adipocytes, its expression has been detected in other tissues such as endothelial cells [3] and human muscles [4]. While PI3K/Akt signaling pathway is mainly responsible for evoked Glut translocation and glucose utilization [6], AMP-activated protein kinase (AMPK) plays a predominant role in stimulating glucose uptake during exercise via activation of p38 MAPK [7,8]. In response to a fall in intracellular ATP level, AMPK activates energy-producing processes such as glucose uptake, fatty acid oxidation and glycolysis, while inhibiting energy-consuming processes such as lipogenesis, protein synthesis and gluconeogenesis [10]

Methods

Results

Conclusion