Therapeutic potential of PPAR-α/γ dual agonist with alleviation of ER stress for the treatment of diabetes mellitus

Abstract

Objective: Peroxisome proliferator-activated receptor-α/γ (PPARα/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 antidiabetic effects in animal model.

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 antidiabetic effects and elucidate its molecular mechanisms.

Results: Macelignan reduced serum glucose, insulin, triglyceride (TG), free fatty acids (FFAs) levels, and TG 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 tissues and serum, whereas the expression and serum levels of TNF-α and IL-6 decreased. Macelignan downregulated inflammatory gene expression in the liver, and increased AMP-activated protein kinase (AMPK) activation in the skeletal muscle of db/db mice. Strikingly, macelignan reduced endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK) activation in the liver and adipose tissues of db/db mice, and subsequently increased insulin signaling.

Conclusions: Macelignan enhanced insulin sensitivity and improved lipid metabolic disorders by activating PPARα/γ and attenuating ER stress, suggesting it has potential as an antidiabetic agent for the treatment of type 2 diabetes.