Halofenate is a selective peroxisome proliferator-activated receptor [gamma] modulator with antidiabetic activity
Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that h...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2006-09, Vol.55 (9), p.2523 |
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| creator | Allen, Tamara Zhang, Fang Moodie, Shonna A Clemens, L. Edward Smith, Aaron Gregoire, Francine Bell, Andrea Muscat, George E.O Gustafson, Thomas A |
| description | Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-[gamma] modulator (SPPAR[gamma]M). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-[gamma]. Reporter assays show that HA is a partial PPAR-[gamma] agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-[gamma]-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/ fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPAR[gamma]M with promising therapeutic utility with the potential for less weight gain. |
| doi_str_mv | 10.2337/db06-0618 |
| format | Article |
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Edward ; Smith, Aaron ; Gregoire, Francine ; Bell, Andrea ; Muscat, George E.O ; Gustafson, Thomas A</creator><creatorcontrib>Allen, Tamara ; Zhang, Fang ; Moodie, Shonna A ; Clemens, L. Edward ; Smith, Aaron ; Gregoire, Francine ; Bell, Andrea ; Muscat, George E.O ; Gustafson, Thomas A</creatorcontrib><description>Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-[gamma] modulator (SPPAR[gamma]M). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-[gamma]. Reporter assays show that HA is a partial PPAR-[gamma] agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-[gamma]-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/ fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPAR[gamma]M with promising therapeutic utility with the potential for less weight gain.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db06-0618</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>New York: American Diabetes Association</publisher><subject>Antidiabetics ; Body fat ; Cloning ; Diabetes ; Edema ; Gene expression ; Genetic aspects ; Glucose ; Hyperlipidemia ; Insulin ; Ligands ; Peroxisomes ; Plasmids ; Triglycerides ; Type 2 diabetes</subject><ispartof>Diabetes (New York, N.Y.), 2006-09, Vol.55 (9), p.2523</ispartof><rights>COPYRIGHT 2006 American Diabetes Association</rights><rights>Copyright American Diabetes Association Sep 2006</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>314,776,780,27903,27904</link.rule.ids></links><search><creatorcontrib>Allen, Tamara</creatorcontrib><creatorcontrib>Zhang, Fang</creatorcontrib><creatorcontrib>Moodie, Shonna A</creatorcontrib><creatorcontrib>Clemens, L. Edward</creatorcontrib><creatorcontrib>Smith, Aaron</creatorcontrib><creatorcontrib>Gregoire, Francine</creatorcontrib><creatorcontrib>Bell, Andrea</creatorcontrib><creatorcontrib>Muscat, George E.O</creatorcontrib><creatorcontrib>Gustafson, Thomas A</creatorcontrib><title>Halofenate is a selective peroxisome proliferator-activated receptor [gamma] modulator with antidiabetic activity</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-[gamma] modulator (SPPAR[gamma]M). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-[gamma]. Reporter assays show that HA is a partial PPAR-[gamma] agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-[gamma]-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/ fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPAR[gamma]M with promising therapeutic utility with the potential for less weight gain.</description><subject>Antidiabetics</subject><subject>Body fat</subject><subject>Cloning</subject><subject>Diabetes</subject><subject>Edema</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Glucose</subject><subject>Hyperlipidemia</subject><subject>Insulin</subject><subject>Ligands</subject><subject>Peroxisomes</subject><subject>Plasmids</subject><subject>Triglycerides</subject><subject>Type 2 diabetes</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</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>eNotjk9LAzEQxYMoWKsHv0HwHs2f3WT3WIpaodCLgiCyTHZn15R00-6mWr-9qcocZpj5vTePkGvBb6VS5q6xXDOuRXFCJqJUJVPSvJ6SCedCMmFKc04uxnHNOdepJmS3AB9a7CEidSMFOqLHOrpPpFscwsGNYZPGIXjX4gAxDAyO58Q3dMAat2lF3zrYbOCdbkKz90eIfrn4QaGPrnFgMbqa_spc_L4kZy34Ea_--5S8PNw_zxdsuXp8ms-WrBMqjyzjGpQAq4QB3giFWdEYXeZ1I6WwaKXOjNZQgmi5xMJYXhcWWmNzU1jJMzUlN3--Kfxuj2Os1mE_9OllJUUSm0KpBLE_qAOPlevr0Ec8xDp4jx1WKdB8Vc1ELjQ3hc7UD_WZbEc</recordid><startdate>20060901</startdate><enddate>20060901</enddate><creator>Allen, Tamara</creator><creator>Zhang, Fang</creator><creator>Moodie, Shonna A</creator><creator>Clemens, L. Edward</creator><creator>Smith, Aaron</creator><creator>Gregoire, Francine</creator><creator>Bell, Andrea</creator><creator>Muscat, George E.O</creator><creator>Gustafson, Thomas A</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>20060901</creationdate><title>Halofenate is a selective peroxisome proliferator-activated receptor [gamma] modulator with antidiabetic activity</title><author>Allen, Tamara ; Zhang, Fang ; Moodie, Shonna A ; Clemens, L. Edward ; Smith, Aaron ; Gregoire, Francine ; Bell, Andrea ; Muscat, George E.O ; Gustafson, Thomas A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g135t-406a31ab317a0d13e48d7695cd221beb264766a9a1f02e87b0c8baf7b578b2043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Antidiabetics</topic><topic>Body fat</topic><topic>Cloning</topic><topic>Diabetes</topic><topic>Edema</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Glucose</topic><topic>Hyperlipidemia</topic><topic>Insulin</topic><topic>Ligands</topic><topic>Peroxisomes</topic><topic>Plasmids</topic><topic>Triglycerides</topic><topic>Type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Allen, Tamara</creatorcontrib><creatorcontrib>Zhang, Fang</creatorcontrib><creatorcontrib>Moodie, Shonna A</creatorcontrib><creatorcontrib>Clemens, L. Edward</creatorcontrib><creatorcontrib>Smith, Aaron</creatorcontrib><creatorcontrib>Gregoire, Francine</creatorcontrib><creatorcontrib>Bell, Andrea</creatorcontrib><creatorcontrib>Muscat, George E.O</creatorcontrib><creatorcontrib>Gustafson, Thomas A</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>Allen, Tamara</au><au>Zhang, Fang</au><au>Moodie, Shonna A</au><au>Clemens, L. Edward</au><au>Smith, Aaron</au><au>Gregoire, Francine</au><au>Bell, Andrea</au><au>Muscat, George E.O</au><au>Gustafson, Thomas A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Halofenate is a selective peroxisome proliferator-activated receptor [gamma] modulator with antidiabetic activity</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2006-09-01</date><risdate>2006</risdate><volume>55</volume><issue>9</issue><spage>2523</spage><pages>2523-</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-[gamma] modulator (SPPAR[gamma]M). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-[gamma]. Reporter assays show that HA is a partial PPAR-[gamma] agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-[gamma]-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/ fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPAR[gamma]M with promising therapeutic utility with the potential for less weight gain.</abstract><cop>New York</cop><pub>American Diabetes Association</pub><doi>10.2337/db06-0618</doi></addata></record> |
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| ispartof | Diabetes (New York, N.Y.), 2006-09, Vol.55 (9), p.2523 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_proquest_journals_216477833 |
| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Antidiabetics Body fat Cloning Diabetes Edema Gene expression Genetic aspects Glucose Hyperlipidemia Insulin Ligands Peroxisomes Plasmids Triglycerides Type 2 diabetes |
| title | Halofenate is a selective peroxisome proliferator-activated receptor [gamma] modulator with antidiabetic activity |
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