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lüll Therapeutic potential of peroxisome proliferators--activated receptor-alpha/gamma dual agonist with alleviation of endoplasmic reticulum stress for the treatment of diabetes Han KL; Choi JS; Lee JY; Song J; Joe MK; Jung MH; Hwang JKDiabetes 2008[Mar]; 57 (3): 737-45OBJECTIVE: Peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonists have the potential to be used as therapeutic agents for the treatment of type 2 diabetes. This study evaluated the function of macelignan, a natural compound isolated from Myristica fragrans, as a dual agonist for PPARalpha/gamma and investigated its antidiabetes effects in animal models. RESEARCH DESIGN AND METHODS: GAL4/PPAR chimera transactivation was performed and the expression of PPARalpha/gamma target genes was monitored to examine the ability of macelignan to activate PPARalpha/gamma. Additionally, macelignan was administrated to obese diabetic (db/db) mice to investigate antidiabetes effects and elucidate its molecular mechanisms. RESULTS: Macelignan reduced serum glucose, insulin, triglycerides, free fatty acid levels, and triglycerides levels in the skeletal muscle and liver of db/db mice. Furthermore, macelignan significantly improved glucose and insulin tolerance in these mice, and without altering food intake, their body weights were slightly reduced while weights of troglitazone-treated mice increased. Macelignan increased adiponectin expression in adipose tissue and serum, whereas the expression and serum levels of tumor necrosis factor-alpha and interleukin-6 decreased. Macelignan downregulated inflammatory gene expression in the liver and increased AMP-activated protein kinase activation in the skeletal muscle of db/db mice. Strikingly, macelignan reduced endoplasmic reticulum (ER) stress and c-Jun NH(2)-terminal kinase activation in the liver and adipose tissue of db/db mice and subsequently increased insulin signaling. CONCLUSIONS: Macelignan enhanced insulin sensitivity and improved lipid metabolic disorders by activating PPARalpha/gamma and attenuating ER stress, suggesting that it has potential as an antidiabetes agent for the treatment of type 2 diabetes.|Adaptor Proteins, Signal Transducing/metabolism[MESH]|Adipose Tissue, White/drug effects/metabolism[MESH]|Animals[MESH]|Cell Line[MESH]|Diabetes Mellitus, Type 2/*drug therapy[MESH]|Endoplasmic Reticulum/*drug effects[MESH]|Insulin Receptor Substrate Proteins[MESH]|Lignans/chemistry/*pharmacology/*therapeutic use[MESH]|Liver/drug effects/metabolism[MESH]|Mice[MESH]|Mice, Obese[MESH]|Molecular Structure[MESH]|Myristica/chemistry[MESH]|PPAR alpha/*agonists[MESH]|PPAR gamma/*agonists[MESH]|Stress, Physiological[MESH]|Thapsigargin[MESH] |