Therapeutic Potential of Peroxisome Proliferators–Activated Receptor-α/γ Dual Agonist With Alleviation of Endoplasmic Reticulum Stress for the Treatment of Diabetes

Therapeutic Potential of Peroxisome Proliferators–Activated Receptor-α/γ Dual Agonist With Alleviation of Endoplasmic Reticulum Stress for the Treatment of Diabetes Kyu Lee Han 1 , 2 , Joo Sun Choi 2 , Jae Young Lee 1 , Jihyun Song 2 , Myung Kuk Joe 2 , Myeong Ho Jung 2 , 3 and Jae-Kwan Hwang 1 1 Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul, South Korea 2 Division of Metabolic Disease, Department of Biomedical Science, National Institutes of Health, Seoul, South Korea 3 School of Oriental Medicine, Pusan National University, Busan, South Korea Address correspondence and reprint requests to Prof. Myeong Ho Jung, School of Oriental Medicine, 30 Jangjeon-dong, Geumjeong-gu, Busan 609-735, South Korea. E-mail: jung0603{at}pusan.ac.kr ; and Prof. Jae-Kwan Hwang, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120-749, South Korea. E-mail: jkhwang{at}yonsei.ac.kr Abstract OBJECTIVE— Peroxisome proliferator–activated receptor (PPAR) α/γ 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 PPARα/γ and investigated its antidiabetes effects in animal models. RESEARCH DESIGN AND METHODS— GAL4/PPAR chimera transactivation was performed and the expression of PPARα/γ target genes was monitored to examine the ability of macelignan to activate PPARα/γ. 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-α 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 s