Low Molecular Weight Fucoidan Improves Endoplasmic Reticulum Stress-Reduced Insulin Sensitivity through AMP-Activated Protein Kinase Activation in L6 Myotubes and Restores Lipid Homeostasis in a Mouse Model of Type 2 Diabetes

Abstract

Low molecular weight fucoidan (LMWF) is widely used to treat metabolic disorders, but its physiologic effects have not been well determined. In the present study, we investigated the metabolic effects of LMWF in obese diabetic mice (leptin receptor-deficient db/db mice) and the underlying molecular mechanisms involved in endoplasmic reticulum (ER) stressresponsive L6 myotubes. The effect of LMWF-mediated AMP-activated protein kinase (AMPK) activation on insulin resistance via regulation of the ER stress-dependent pathway was examined in vitro and in vivo. In db/db mice, LMWF markedly reduced serum glucose, triglyceride, cholesterol, and low-density lipoprotein levels, and gradually reduced body weights by reducing lipid parameters. Furthermore, it effectively ameliorated glucose homeostasis by elevating glucose tolerance. In addition, the phosphorylation levels of AMPK and Akt were markedly reduced by ER stressor, and subsequently, glucose uptake and fatty acid oxidation were also reduced. However, these adverse effects of ER stress were significantly ameliorated by LMWF. Finally, in L6 myotubes, LMWF markedly reduced the ER stress-induced upregulation of the mammalian target of rapamycin-p70S61 kinase network and subsequently improved the action of insulin via AMPK stimulation. Our findings suggest that AMPK activation by LMWF could prevent metabolic diseases by controlling the ER stress-dependent pathway and that this beneficial effect of LMWF provides a potential therapeutic strategy for ameliorating ER stress-mediated metabolic dysfunctions.

Low-molecular-weight fucoidan protects endothelial function and ameliorates basal hypertension in diabetic Goto-Kakizaki rats

“…In addition, Jeong et al found that LMWF improves insulin sensitivity through AMPK activation and restores lipid homeostasis in a mouse model of type 2 diabetes. 48 Thus, this may be one of the mechanisms that explain its activation of eNOS phosphorylation; however, further and more detailed studies are necessary regarding how LMWF improves endothelial dysfunction in diabetes. In addition, it appears that LMWF demonstrated a dosedependent but not proportional effect on endothelium damage in diabetic rats.…”

Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK

“…Blood glucose levels of all mice were measured with Glucostix AccuCheck (Roche Diagnostics, Mannheim, Germany), and blood ethanol levels were quantified with Ethanol assay kit (Sigma-Aldrich). Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and cholesterol were determined with an automated blood analyzer (AU400; Olympus, Tokyo, Japan) [21]. Total adiponectin levels were measured using a commercial ELISA kit from R&D Systems (Minnesotapolis, MN, USA), and insulin levels were analyzed with the insulin enzyme-linked immunosorbent assay test kit (Mercodia, Uppsala, Sweden).…”

“…Hepatic and serum bile acid (BA) were measured with Bile acid L3K assay kit (Cell Biolabs, Inc., San Diego, CA, USA). Serum cytokine concentrations were measured using a BD Cytometry Bead Array (BD Bioscience, San Jose, CA, USA) in accordance with the manufacturer's instructions, as described previously [21].…”

“…Total TG levels in liver were analyzed using Infinity reagents (Thermo DMA, Louisville, CO, USA), according to the manufacturer's protocol, as mentioned previously [21,22]. Serum TG levels were measured using a commercially available determination kits (Sigma-Aldrich).…”

“…For hematoxylin and eosin (H & E) staining, liver tissue samples were fixed with 4% paraformaldehyde and embedded with paraffin, as described previously [21,22]. Liver sections (4-5 μm) were performed with H & E staining according to the standard procedures.…”