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) stress-responsive 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.

• Authors: Yong-Tae Jeong, Yong Deuk Kim, Young-Mi Jung, Dong-Chan Park, Dong-Sub Lee, Sae-Kwang Ku, Xian Li, Yue Lu, Guang Hsuan Chao, Keuk-Jun Kim, Jai-Youl Lee, Moon-Chang Baek, Wonku Kang, Seung-Lark Hwang, Hyeun Wook Chang
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 84 Issue 1 Pg. 147-57 (Jul 2013) ISSN: 1521-0111 [Electronic] United States
• PMID: 23658008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipids
• Lipoproteins, LDL
• Polysaccharides
• Triglycerides
• fucoidan
• Cholesterol
• Proto-Oncogene Proteins c-akt
• AMP-Activated Protein Kinases
• Glucose

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Body Weight
• Cholesterol (blood)
• Diabetes Mellitus, Experimental (drug therapy, metabolism)
• Diabetes Mellitus, Type 2 (drug therapy, metabolism)
• Endoplasmic Reticulum Stress (drug effects)
• Glucose (metabolism)
• Homeostasis (drug effects)
• Insulin Resistance (physiology)
• Lipid Metabolism (drug effects)
• Lipids
• Lipoproteins, LDL (blood)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Molecular Weight
• Muscle Fibers, Skeletal (drug effects, metabolism)
• Phosphorylation (drug effects)
• Polysaccharides (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Triglycerides (blood)