Therapeutic Potential of Peroxisome Proliferators-Activated Receptor-[alpha]/[gamma] Dual Agonist With Alleviation of Endoplasmic Reticulum Stress for the Treatment of Diabetes
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/...
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Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2008-03, Vol.57 (3), p.737 |
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description | 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. 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. 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. 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. |
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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. 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. 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. 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.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>New York: American Diabetes Association</publisher><subject>Body fat ; Diabetes ; Endoplasmic reticulum ; Fatty acids ; Glucose ; Hyperlipidemia ; Insulin resistance ; Kinases ; Laboratory animals ; Lipids ; Liver ; Metabolism ; Musculoskeletal system ; Natural products ; Proteins ; Research design ; Triglycerides ; Tumor necrosis factor-TNF</subject><ispartof>Diabetes (New York, N.Y.), 2008-03, Vol.57 (3), p.737</ispartof><rights>Copyright American Diabetes Association Mar 2008</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids></links><search><creatorcontrib>Han, Kyu Lee</creatorcontrib><creatorcontrib>Choi, Joo Sun</creatorcontrib><creatorcontrib>Lee, Jae Young</creatorcontrib><creatorcontrib>Song, Jihyun</creatorcontrib><creatorcontrib>Joe, Myung Kuk</creatorcontrib><creatorcontrib>Jung, Myeong Ho</creatorcontrib><creatorcontrib>Hwang, Jae-Kwan</creatorcontrib><title>Therapeutic Potential of Peroxisome Proliferators-Activated Receptor-[alpha]/[gamma] Dual Agonist With Alleviation of Endoplasmic Reticulum Stress for the Treatment of Diabetes</title><title>Diabetes (New York, N.Y.)</title><description>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. 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. 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. 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.</description><subject>Body fat</subject><subject>Diabetes</subject><subject>Endoplasmic reticulum</subject><subject>Fatty acids</subject><subject>Glucose</subject><subject>Hyperlipidemia</subject><subject>Insulin resistance</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Lipids</subject><subject>Liver</subject><subject>Metabolism</subject><subject>Musculoskeletal system</subject><subject>Natural products</subject><subject>Proteins</subject><subject>Research design</subject><subject>Triglycerides</subject><subject>Tumor necrosis factor-TNF</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNjt1Kw0AQhRdRMP68w-B9MJuUhlwGW_Ey1IJCKWVMJ82WTSbuzhYfy0d0Cz5AmYsDc745Z65UoquiSou8_LxWSZbpPNVlVd6qO--PWZbN4yTqd92Tw4mCmBYaFhrFoAXuoCHHP8bzQNA4tqaLnLDzad2KOaHQHlbU0hR36Qbt1OP2eXPAYcAtLELMqA88Gi_wYaSH2lo6GRTD4zl8Oe55suiH2Lqi2B1sGOBdHHkPHTuQnmDtCGWIH50vFga_SMg_qJsOrafHf71XT6_L9ctbOjn-DuRld-Tgxmjtcj2fVTOt8-Ii6A_pgmRI</recordid><startdate>20080301</startdate><enddate>20080301</enddate><creator>Han, Kyu Lee</creator><creator>Choi, Joo Sun</creator><creator>Lee, Jae Young</creator><creator>Song, Jihyun</creator><creator>Joe, Myung Kuk</creator><creator>Jung, Myeong Ho</creator><creator>Hwang, Jae-Kwan</creator><general>American Diabetes Association</general><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope></search><sort><creationdate>20080301</creationdate><title>Therapeutic Potential of Peroxisome Proliferators-Activated Receptor-[alpha]/[gamma] Dual Agonist With Alleviation of Endoplasmic Reticulum Stress for the Treatment of Diabetes</title><author>Han, Kyu Lee ; Choi, Joo Sun ; Lee, Jae Young ; Song, Jihyun ; Joe, Myung Kuk ; Jung, Myeong Ho ; Hwang, Jae-Kwan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_2164941123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Body fat</topic><topic>Diabetes</topic><topic>Endoplasmic reticulum</topic><topic>Fatty acids</topic><topic>Glucose</topic><topic>Hyperlipidemia</topic><topic>Insulin resistance</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Lipids</topic><topic>Liver</topic><topic>Metabolism</topic><topic>Musculoskeletal system</topic><topic>Natural products</topic><topic>Proteins</topic><topic>Research design</topic><topic>Triglycerides</topic><topic>Tumor necrosis factor-TNF</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Han, Kyu Lee</creatorcontrib><creatorcontrib>Choi, Joo Sun</creatorcontrib><creatorcontrib>Lee, Jae Young</creatorcontrib><creatorcontrib>Song, Jihyun</creatorcontrib><creatorcontrib>Joe, Myung Kuk</creatorcontrib><creatorcontrib>Jung, Myeong Ho</creatorcontrib><creatorcontrib>Hwang, Jae-Kwan</creatorcontrib><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Han, Kyu Lee</au><au>Choi, Joo Sun</au><au>Lee, Jae Young</au><au>Song, Jihyun</au><au>Joe, Myung Kuk</au><au>Jung, Myeong Ho</au><au>Hwang, Jae-Kwan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Therapeutic Potential of Peroxisome Proliferators-Activated Receptor-[alpha]/[gamma] Dual Agonist With Alleviation of Endoplasmic Reticulum Stress for the Treatment of Diabetes</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><date>2008-03-01</date><risdate>2008</risdate><volume>57</volume><issue>3</issue><spage>737</spage><pages>737-</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>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. 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. 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. 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.</abstract><cop>New York</cop><pub>American Diabetes Association</pub></addata></record> |
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subjects | Body fat Diabetes Endoplasmic reticulum Fatty acids Glucose Hyperlipidemia Insulin resistance Kinases Laboratory animals Lipids Liver Metabolism Musculoskeletal system Natural products Proteins Research design Triglycerides Tumor necrosis factor-TNF |
title | Therapeutic Potential of Peroxisome Proliferators-Activated Receptor-[alpha]/[gamma] Dual Agonist With Alleviation of Endoplasmic Reticulum Stress for the Treatment of Diabetes |
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