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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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2003-08, Vol.100 (17), p.10067-10072
Hauptverfasser: 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.
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container_end_page 10072
container_issue 17
container_start_page 10067
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 100
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
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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.$3,5,3^\prime\!-\!triiodi\!-\!{\scriptstyle L}\!-\!thyronine\&gt;(T_3)$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$-\!\beta.\&gt;T_3$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. 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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.$3,5,3^\prime\!-\!triiodi\!-\!{\scriptstyle L}\!-\!thyronine\&gt;(T_3)$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$-\!\beta.\&gt;T_3$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 &amp; 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. ; 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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.$3,5,3^\prime\!-\!triiodi\!-\!{\scriptstyle L}\!-\!thyronine\&gt;(T_3)$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$-\!\beta.\&gt;T_3$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