Selective Thyroid Hormone Receptor-β Activation: A Strategy for Reduction of Weight, Cholesterol, and Lipoprotein (a) with Reduced Cardiovascular Liability
Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the...
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creator | Grover, Gary J. Mellström, Karin Ye, Liu Malm, Johan Li, Yi-Lin Bladh, Lars-Göran Sleph, Paul G. Smith, Mark A. George, Rocco Vennström, Björn Mookhtiar, Kasim Horvath, Ryan Speelman, Jessica Egan, Donald Baxter, John D. |
description | Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TRβ subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TRα appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TRβ activation on metabolic rate and HR with either TRα1
-/-mice or the selective TRβ agonist KB-141 in mice, rats, and monkeys.$3,5,3^\prime\!-\!triiodi\!-\!{\scriptstyle L}\!-\!thyronine\>(T_3)$had a greater effect on increasing HR in WT than in TRα-/-mice (ED15values of 34 and 469 nmol/kg/day, respectively). T3increased metabolic rate [whole body oxygen consumption (MVO2
)] in both WT and TRα-/-mice, but the effect in the TRα1
-/-mice at the highest dose was half that of the WT mice. Thus, stimulation of MVO2
is likely due to both TRα and$-\!\beta.\>T_3$had equivalent potency for cholesterol reduction in WT and TRα-/-mice. KB-141 increased MVO2
with selectivities of 16.5- and 11.2-fold vs. HR in WT and TRα1
-/-mice, respectively. KB-141 also increased MVO2
with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TRβ-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a). |
doi_str_mv | 10.1073/pnas.1633737100 |
format | Article |
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-/-mice or the selective TRβ agonist KB-141 in mice, rats, and monkeys.$3,5,3^\prime\!-\!triiodi\!-\!{\scriptstyle L}\!-\!thyronine\>(T_3)$had a greater effect on increasing HR in WT than in TRα-/-mice (ED15values of 34 and 469 nmol/kg/day, respectively). T3increased metabolic rate [whole body oxygen consumption (MVO2
)] in both WT and TRα-/-mice, but the effect in the TRα1
-/-mice at the highest dose was half that of the WT mice. Thus, stimulation of MVO2
is likely due to both TRα and$-\!\beta.\>T_3$had equivalent potency for cholesterol reduction in WT and TRα-/-mice. KB-141 increased MVO2
with selectivities of 16.5- and 11.2-fold vs. HR in WT and TRα1
-/-mice, respectively. KB-141 also increased MVO2
with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TRβ-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1633737100</identifier><identifier>PMID: 12888625</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Agonists ; Animals ; Anticholesteremic Agents - pharmacology ; Biological Sciences ; Blood plasma ; Body temperature ; Body weight ; Cardiovascular disease ; Cardiovascular System - drug effects ; Cholesterol ; Cholesterol - blood ; Cholesterol metabolism ; Cholesterol, Dietary - administration & dosage ; Cholesterols ; Hormones ; Humans ; In Vitro Techniques ; Kinetics ; Lipoprotein(a) - blood ; Lipoproteins ; Macaca fascicularis ; Mice ; Mice, Knockout ; Phenyl Ethers - pharmacology ; Phenylacetates - pharmacology ; Proteins ; Rats ; Rats, Sprague-Dawley ; Receptors, Thyroid Hormone - agonists ; Receptors, Thyroid Hormone - metabolism ; Tachycardia ; Thyroid gland ; Thyroid Hormone Receptors alpha - deficiency ; Thyroid Hormone Receptors alpha - genetics ; Thyroid Hormone Receptors beta ; Thyroid hormones ; Triiodothyronine - pharmacology ; Weight ; Weight Loss - drug effects</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2003-08, Vol.100 (17), p.10067-10072</ispartof><rights>Copyright 1993-2003 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Aug 19, 2003</rights><rights>Copyright © 2003, The National Academy of Sciences 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c564t-c298fe1b6c336802beaa5cfd6253fa32d326c1c22d98d33fc53f9a18eb4b0b403</citedby><cites>FETCH-LOGICAL-c564t-c298fe1b6c336802beaa5cfd6253fa32d326c1c22d98d33fc53f9a18eb4b0b403</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/100/17.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3147663$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3147663$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,550,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12888625$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:1930494$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Grover, Gary J.</creatorcontrib><creatorcontrib>Mellström, Karin</creatorcontrib><creatorcontrib>Ye, Liu</creatorcontrib><creatorcontrib>Malm, Johan</creatorcontrib><creatorcontrib>Li, Yi-Lin</creatorcontrib><creatorcontrib>Bladh, Lars-Göran</creatorcontrib><creatorcontrib>Sleph, Paul G.</creatorcontrib><creatorcontrib>Smith, Mark A.</creatorcontrib><creatorcontrib>George, Rocco</creatorcontrib><creatorcontrib>Vennström, Björn</creatorcontrib><creatorcontrib>Mookhtiar, Kasim</creatorcontrib><creatorcontrib>Horvath, Ryan</creatorcontrib><creatorcontrib>Speelman, Jessica</creatorcontrib><creatorcontrib>Egan, Donald</creatorcontrib><creatorcontrib>Baxter, John D.</creatorcontrib><title>Selective Thyroid Hormone Receptor-β Activation: A Strategy for Reduction of Weight, Cholesterol, and Lipoprotein (a) with Reduced Cardiovascular Liability</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TRβ subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TRα appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TRβ activation on metabolic rate and HR with either TRα1
-/-mice or the selective TRβ agonist KB-141 in mice, rats, and monkeys.$3,5,3^\prime\!-\!triiodi\!-\!{\scriptstyle L}\!-\!thyronine\>(T_3)$had a greater effect on increasing HR in WT than in TRα-/-mice (ED15values of 34 and 469 nmol/kg/day, respectively). T3increased metabolic rate [whole body oxygen consumption (MVO2
)] in both WT and TRα-/-mice, but the effect in the TRα1
-/-mice at the highest dose was half that of the WT mice. Thus, stimulation of MVO2
is likely due to both TRα and$-\!\beta.\>T_3$had equivalent potency for cholesterol reduction in WT and TRα-/-mice. KB-141 increased MVO2
with selectivities of 16.5- and 11.2-fold vs. HR in WT and TRα1
-/-mice, respectively. KB-141 also increased MVO2
with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TRβ-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).</description><subject>Agonists</subject><subject>Animals</subject><subject>Anticholesteremic Agents - pharmacology</subject><subject>Biological Sciences</subject><subject>Blood plasma</subject><subject>Body temperature</subject><subject>Body weight</subject><subject>Cardiovascular disease</subject><subject>Cardiovascular System - drug effects</subject><subject>Cholesterol</subject><subject>Cholesterol - blood</subject><subject>Cholesterol metabolism</subject><subject>Cholesterol, Dietary - administration & dosage</subject><subject>Cholesterols</subject><subject>Hormones</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Kinetics</subject><subject>Lipoprotein(a) - blood</subject><subject>Lipoproteins</subject><subject>Macaca fascicularis</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Phenyl Ethers - pharmacology</subject><subject>Phenylacetates - pharmacology</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Thyroid Hormone - agonists</subject><subject>Receptors, Thyroid Hormone - metabolism</subject><subject>Tachycardia</subject><subject>Thyroid gland</subject><subject>Thyroid Hormone Receptors alpha - deficiency</subject><subject>Thyroid Hormone Receptors alpha - genetics</subject><subject>Thyroid Hormone Receptors beta</subject><subject>Thyroid hormones</subject><subject>Triiodothyronine - pharmacology</subject><subject>Weight</subject><subject>Weight Loss - drug effects</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNqFkt1u0zAUxyMEYt3gmhuELC4mJi2bP5LYQeKiqoAhVUJiQ1xajnPSuqRxsJ2OvgtPwYPwTDhqtTJudnUsn9__6Hz8k-QFwRcEc3bZd8pfkIIxzjjB-FEyIbgkaZGV-HEywZjyVGQ0O0qOvV9hjMtc4KfJEaFCiILmk-TXNbSgg9kAullunTU1urJubTtAX0BDH6xL__xG0xFRwdjuLZqi6-BUgMUWNdZFrB70mEG2Qd_ALJbhHM2WtgUfwNn2HKmuRnPT297ZAKZDb9QZujVhuZNCjWbK1cZulNdDq1xkVWVaE7bPkieNaj0838eT5OuH9zezq3T--eOn2XSe6rzIQqppKRogVaEZKwSmFSiV66aOA7JGMVozWmiiKa1LUTPW6PhdKiKgyipcZZidJOmurr-Ffqhk78xaua20ysj91_f4ApkLUeY08u92fMysodbQxYW092T3M51ZyoXdSCI4L0TUn-71zv4Y4p7k2ngNbas6sIOXnOWc5rH7h0AiBCnjgSP4-j9wZQfXxaVJisdrs5xF6HIHaWe9d9DcdUywHO0kRzvJg52i4tW_gx74vX8igPbAqDyUi_X4GAoekbMHENkMbRvgZ4jsyx278tF4dzAjGS9iV38BlV3skA</recordid><startdate>20030819</startdate><enddate>20030819</enddate><creator>Grover, Gary J.</creator><creator>Mellström, Karin</creator><creator>Ye, Liu</creator><creator>Malm, Johan</creator><creator>Li, Yi-Lin</creator><creator>Bladh, Lars-Göran</creator><creator>Sleph, Paul G.</creator><creator>Smith, Mark A.</creator><creator>George, Rocco</creator><creator>Vennström, Björn</creator><creator>Mookhtiar, Kasim</creator><creator>Horvath, Ryan</creator><creator>Speelman, Jessica</creator><creator>Egan, Donald</creator><creator>Baxter, John D.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20030819</creationdate><title>Selective Thyroid Hormone Receptor-β Activation: A Strategy for Reduction of Weight, Cholesterol, and Lipoprotein (a) with Reduced Cardiovascular Liability</title><author>Grover, Gary J. ; Mellström, Karin ; Ye, Liu ; Malm, Johan ; Li, Yi-Lin ; Bladh, Lars-Göran ; Sleph, Paul G. ; Smith, Mark A. ; George, Rocco ; Vennström, Björn ; Mookhtiar, Kasim ; Horvath, Ryan ; Speelman, Jessica ; Egan, Donald ; Baxter, John D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c564t-c298fe1b6c336802beaa5cfd6253fa32d326c1c22d98d33fc53f9a18eb4b0b403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Agonists</topic><topic>Animals</topic><topic>Anticholesteremic Agents - pharmacology</topic><topic>Biological Sciences</topic><topic>Blood plasma</topic><topic>Body temperature</topic><topic>Body weight</topic><topic>Cardiovascular disease</topic><topic>Cardiovascular System - drug effects</topic><topic>Cholesterol</topic><topic>Cholesterol - blood</topic><topic>Cholesterol metabolism</topic><topic>Cholesterol, Dietary - administration & dosage</topic><topic>Cholesterols</topic><topic>Hormones</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Kinetics</topic><topic>Lipoprotein(a) - blood</topic><topic>Lipoproteins</topic><topic>Macaca fascicularis</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Phenyl Ethers - pharmacology</topic><topic>Phenylacetates - pharmacology</topic><topic>Proteins</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Thyroid Hormone - agonists</topic><topic>Receptors, Thyroid Hormone - metabolism</topic><topic>Tachycardia</topic><topic>Thyroid gland</topic><topic>Thyroid Hormone Receptors alpha - deficiency</topic><topic>Thyroid Hormone Receptors alpha - genetics</topic><topic>Thyroid Hormone Receptors beta</topic><topic>Thyroid hormones</topic><topic>Triiodothyronine - pharmacology</topic><topic>Weight</topic><topic>Weight Loss - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grover, Gary J.</creatorcontrib><creatorcontrib>Mellström, Karin</creatorcontrib><creatorcontrib>Ye, Liu</creatorcontrib><creatorcontrib>Malm, Johan</creatorcontrib><creatorcontrib>Li, Yi-Lin</creatorcontrib><creatorcontrib>Bladh, Lars-Göran</creatorcontrib><creatorcontrib>Sleph, Paul G.</creatorcontrib><creatorcontrib>Smith, Mark A.</creatorcontrib><creatorcontrib>George, Rocco</creatorcontrib><creatorcontrib>Vennström, Björn</creatorcontrib><creatorcontrib>Mookhtiar, Kasim</creatorcontrib><creatorcontrib>Horvath, Ryan</creatorcontrib><creatorcontrib>Speelman, Jessica</creatorcontrib><creatorcontrib>Egan, Donald</creatorcontrib><creatorcontrib>Baxter, John D.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grover, Gary J.</au><au>Mellström, Karin</au><au>Ye, Liu</au><au>Malm, Johan</au><au>Li, Yi-Lin</au><au>Bladh, Lars-Göran</au><au>Sleph, Paul G.</au><au>Smith, Mark A.</au><au>George, Rocco</au><au>Vennström, Björn</au><au>Mookhtiar, Kasim</au><au>Horvath, Ryan</au><au>Speelman, Jessica</au><au>Egan, Donald</au><au>Baxter, John D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective Thyroid Hormone Receptor-β Activation: A Strategy for Reduction of Weight, Cholesterol, and Lipoprotein (a) with Reduced Cardiovascular Liability</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2003-08-19</date><risdate>2003</risdate><volume>100</volume><issue>17</issue><spage>10067</spage><epage>10072</epage><pages>10067-10072</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TRβ subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TRα appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TRβ activation on metabolic rate and HR with either TRα1
-/-mice or the selective TRβ agonist KB-141 in mice, rats, and monkeys.$3,5,3^\prime\!-\!triiodi\!-\!{\scriptstyle L}\!-\!thyronine\>(T_3)$had a greater effect on increasing HR in WT than in TRα-/-mice (ED15values of 34 and 469 nmol/kg/day, respectively). T3increased metabolic rate [whole body oxygen consumption (MVO2
)] in both WT and TRα-/-mice, but the effect in the TRα1
-/-mice at the highest dose was half that of the WT mice. Thus, stimulation of MVO2
is likely due to both TRα and$-\!\beta.\>T_3$had equivalent potency for cholesterol reduction in WT and TRα-/-mice. KB-141 increased MVO2
with selectivities of 16.5- and 11.2-fold vs. HR in WT and TRα1
-/-mice, respectively. KB-141 also increased MVO2
with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TRβ-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>12888625</pmid><doi>10.1073/pnas.1633737100</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; SWEPUB Freely available online; Free Full-Text Journals in Chemistry |
subjects | Agonists Animals Anticholesteremic Agents - pharmacology Biological Sciences Blood plasma Body temperature Body weight Cardiovascular disease Cardiovascular System - drug effects Cholesterol Cholesterol - blood Cholesterol metabolism Cholesterol, Dietary - administration & dosage Cholesterols Hormones Humans In Vitro Techniques Kinetics Lipoprotein(a) - blood Lipoproteins Macaca fascicularis Mice Mice, Knockout Phenyl Ethers - pharmacology Phenylacetates - pharmacology Proteins Rats Rats, Sprague-Dawley Receptors, Thyroid Hormone - agonists Receptors, Thyroid Hormone - metabolism Tachycardia Thyroid gland Thyroid Hormone Receptors alpha - deficiency Thyroid Hormone Receptors alpha - genetics Thyroid Hormone Receptors beta Thyroid hormones Triiodothyronine - pharmacology Weight Weight Loss - drug effects |
title | Selective Thyroid Hormone Receptor-β Activation: A Strategy for Reduction of Weight, Cholesterol, and Lipoprotein (a) with Reduced Cardiovascular Liability |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-17T17%3A21%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Selective%20Thyroid%20Hormone%20Receptor-%CE%B2%20Activation:%20A%20Strategy%20for%20Reduction%20of%20Weight,%20Cholesterol,%20and%20Lipoprotein%20(a)%20with%20Reduced%20Cardiovascular%20Liability&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Grover,%20Gary%20J.&rft.date=2003-08-19&rft.volume=100&rft.issue=17&rft.spage=10067&rft.epage=10072&rft.pages=10067-10072&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.1633737100&rft_dat=%3Cjstor_swepu%3E3147663%3C/jstor_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=201288353&rft_id=info:pmid/12888625&rft_jstor_id=3147663&rfr_iscdi=true |