Therapeutic potential of peroxisome proliferators--activated receptor-alpha/gamma dual agonist with alleviation of endoplasmic reticulum stress for the treatment of diabetes.

Abstract

OBJECTIVE:

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.

• Authors: Kyu Lee Han, Joo Sun Choi, Jae Young Lee, Jihyun Song, Myung Kuk Joe, Myeong Ho Jung, Jae-Kwan Hwang
• Journal: Diabetes (Diabetes) Vol. 57 Issue 3 Pg. 737-45 (Mar 2008) ISSN: 1939-327X [Electronic] United States
• PMID: 18065517 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• Insulin Receptor Substrate Proteins
• Irs1 protein, mouse
• Lignans
• PPAR alpha
• PPAR gamma
• Thapsigargin
• macelignan

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Adipose Tissue, White (drug effects, metabolism)
• Animals
• Cell Line
• Diabetes Mellitus, Type 2 (drug therapy)
• Endoplasmic Reticulum (drug effects)
• Insulin Receptor Substrate Proteins
• Lignans (chemistry, pharmacology, therapeutic use)
• Liver (drug effects, metabolism)
• Mice
• Mice, Obese
• Molecular Structure
• Myristica (chemistry)
• PPAR alpha (agonists)
• PPAR gamma (agonists)
• Stress, Physiological
• Thapsigargin