CYC31, A Natural Bromophenol PTP1B Inhibitor, Activates Insulin Signaling and Improves Long Chain-Fatty Acid Oxidation in C2C12 Myotubes.

Jiao Luo,Bo Jiang,Dayong Shi,Yufei Hou,Mengyue Xie,Wanli Ma

doi:10.3390/md18050267

Abstract

3-bromo-4,5-Bis(2,3-dibromo-4,5-dihydroxybenzyl)-1,2-benzenediol (CYC31) is a bromophenol protein tyrosine phosphatase 1B (PTP1B) inhibitor isolated from the red alga Rhodomela confervoides. Here, the effect of CYC31 on the insulin signaling and fatty-acid-induced disorders in C2C12 myotubes was investigated. Molecular docking assay showed that CYC31 was embedded into the catalytic pocket of PTP1B. A cellular study found that CYC31 increased the activity of insulin signaling and promoted 2-NBDG uptake through GLUT4 translocation in C2C12 myotubes. Further studies showed that CYC31 ameliorated palmitate-induced insulin resistance in C2C12 myotubes. Moreover, CYC31 treatment significantly increased the mRNA expression of carnitine palmitoyltransferase 1B (CPT-1B) and fatty acid binding protein 3 (FABP3), which was tightly linked with fatty acid oxidation. These findings suggested that CYC31 could prevent palmitate-induce insulin resistance and could improve fatty acid oxidation through PTP1B inhibition.

Highlights

Insulin resistance is a common pathological condition in obesity and type 2 diabetes, which is characterized by an impaired response to insulin in peripheral tissues [1,2]
Up to 75% of insulin-dependent glucose is handled by skeletal muscle cells, and muscle plays a central role in whole-body insulin resistance [3]
CYC31 Embeds Into the Catalytic Pocket of protein tyrosine phosphatase 1B (PTP1B)

Summary

Introduction

Insulin resistance is a common pathological condition in obesity and type 2 diabetes, which is characterized by an impaired response to insulin in peripheral tissues [1,2]. The mechanisms underlying the relationship between obesity and skeletal muscle insulin resistance remain controversial, the prevailing theory links insulin resistance to the increasing circulating free fatty acids (FFA) [5]. It is reported that elevated plasma FFA levels in obesity subjects caused insulin resistance in peripheral tissues [6]. The theory demonstrates that mitochondria are critical players in the obesity-linked insulin resistance [7,8]. It is believed that the decrease of mitochondrial fatty acid oxidation caused by mitochondrial dysfunction contributes to insulin resistance development in skeletal muscle [9]

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