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, Joo Sun Choi, Jae Young Lee, Jihyun Song, Myung Kuk Joe, Myeong Ho Jung, Jae Kwan Hwang

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84 Citations (Scopus)

Abstract

OBJECTIVE-Peroxisome proliferator-activated receptor (PPAE) 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 Myristiea 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/γtarget genes was monitored to examine the ability of macelignan to activate PPARα/γAdditionally, 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-αand interleukin-α 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 NH2-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 PPARα/γand attenuating EE stress, suggesting that it has potential as an antidiabetes agent for the treatment of type 2 diabetes.

Original languageEnglish
Pages (from-to)737-745
Number of pages9
JournalDiabetes
Volume57
Issue number3
DOIs
Publication statusPublished - 2008 Mar 1

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All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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