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

Research output: Contribution to journalArticle

78 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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Peroxisome Proliferator-Activated Receptors
Endoplasmic Reticulum Stress
Therapeutics
troglitazone
Insulin
Type 2 Diabetes Mellitus
Adipose Tissue
Liver
Skeletal Muscle
Triglycerides
Serum
macelignan
Glucose
AMP-Activated Protein Kinases
JNK Mitogen-Activated Protein Kinases
Interleukins
Adiponectin
Nonesterified Fatty Acids
Transcriptional Activation
Insulin Resistance

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Han, Kyu Lee ; Choi, Joo Sun ; Lee, Jae Young ; Song, Jihyun ; Joe, Myung Kuk ; Jung, Myeong Ho ; Hwang, Jae-Kwan. / Therapeutic potential of peroxisome proliferators-activated receptor-α/γ dual agonist with alleviation of endoplasmic reticulum stress for the treatment of diabetes. In: Diabetes. 2008 ; Vol. 57, No. 3. pp. 737-745.
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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.",
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Therapeutic potential of peroxisome proliferators-activated receptor-α/γ dual agonist with alleviation of endoplasmic reticulum stress for the treatment of diabetes. / Han, Kyu Lee; Choi, Joo Sun; Lee, Jae Young; Song, Jihyun; Joe, Myung Kuk; Jung, Myeong Ho; Hwang, Jae-Kwan.

In: Diabetes, Vol. 57, No. 3, 01.03.2008, p. 737-745.

Research output: Contribution to journalArticle

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T1 - Therapeutic potential of peroxisome proliferators-activated receptor-α/γ dual agonist with alleviation of endoplasmic reticulum stress for the treatment of diabetes

AU - Han, Kyu Lee

AU - Choi, Joo Sun

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AU - Song, Jihyun

AU - Joe, Myung Kuk

AU - Jung, Myeong Ho

AU - Hwang, Jae-Kwan

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N2 - 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.

AB - 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.

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