Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates: Selective actions relative to 3,5,3′-triiodo-L-thyronine

Gary J. Grover, Donald M. Egan, Paul G. Sleph, Blake C. Beehler, Grazia Chiellini, Ngoc Ha Nguyen, John D. Baxter, Thomas (Tom) Scanlan

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Current drug therapies for obesity are ineffective, and existing treatments for lipid disorders can be further improved. Thyroid hormones affect both conditions, although currently available nonselective thyromimetics are not clinically useful for such treatment due to cardiac side effects. Recent studies suggest that thyroid hormone receptor subtype β(TRβ) selective agonists have a profile in which cholesterol can be reduced with minimal tachycardia. The purpose of this study was to determine whether modest (5-10%) increases in metabolic rate could also be observed with minimal tachycardia after TRβ stimulation. For these studies, the TRβ selective agonist, GC-1, was used to assess selectivity for lipid-lowering and metabolic rate changes relative to tachycardia. Studies in cholesterol-fed rats (7 d treatment) showed that GC-1 reduced cholesterol (ED50 = 190 nmol/kg·d) approximately 30 times more potently than it induced tachycardia (ED15 = 5451 nmol/ kg·d). T3 showed no potency difference between cholesterol lowering and tachycardia. GC-1 showed approximately 10-fold selectivity for increasing metabolic rate (ED5 = 477 nmol/ kg·d) relative to tachycardia compared with T3, which showed no selectivity. In cynomolgus monkeys treated for 7 d, significant cholesterol-lowering and lipoprotein (a) reduction was noted for both T 3 and GC-1, whereas no tachycardia was observed for GC-1, unlike T3. T3 and GC-1 caused a significant (∼4%) reduction in body weight in these animals. Therefore, selective TRβ activation may be a potentially usefully treatment for obesity and reduction of low density lipoprotein cholesterol and reduction of the atherogenic risk factor lipoprotein (a).

Original languageEnglish (US)
Pages (from-to)1656-1661
Number of pages6
JournalEndocrinology
Volume145
Issue number4
DOIs
StatePublished - Apr 2004
Externally publishedYes

Fingerprint

Thyronines
Thyroid Hormone Receptors
Tachycardia
Primates
Cholesterol
Hormones
Lipoprotein(a)
Obesity
Lipids
Macaca fascicularis
GC 1 compound
Thyroid Hormones
LDL Cholesterol
Therapeutics
Body Weight
Drug Therapy

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates : Selective actions relative to 3,5,3′-triiodo-L-thyronine. / Grover, Gary J.; Egan, Donald M.; Sleph, Paul G.; Beehler, Blake C.; Chiellini, Grazia; Nguyen, Ngoc Ha; Baxter, John D.; Scanlan, Thomas (Tom).

In: Endocrinology, Vol. 145, No. 4, 04.2004, p. 1656-1661.

Research output: Contribution to journalArticle

Grover, Gary J. ; Egan, Donald M. ; Sleph, Paul G. ; Beehler, Blake C. ; Chiellini, Grazia ; Nguyen, Ngoc Ha ; Baxter, John D. ; Scanlan, Thomas (Tom). / Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates : Selective actions relative to 3,5,3′-triiodo-L-thyronine. In: Endocrinology. 2004 ; Vol. 145, No. 4. pp. 1656-1661.
@article{1a4f52d8fd8a4faa92bb6b82163849e2,
title = "Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates: Selective actions relative to 3,5,3′-triiodo-L-thyronine",
abstract = "Current drug therapies for obesity are ineffective, and existing treatments for lipid disorders can be further improved. Thyroid hormones affect both conditions, although currently available nonselective thyromimetics are not clinically useful for such treatment due to cardiac side effects. Recent studies suggest that thyroid hormone receptor subtype β(TRβ) selective agonists have a profile in which cholesterol can be reduced with minimal tachycardia. The purpose of this study was to determine whether modest (5-10{\%}) increases in metabolic rate could also be observed with minimal tachycardia after TRβ stimulation. For these studies, the TRβ selective agonist, GC-1, was used to assess selectivity for lipid-lowering and metabolic rate changes relative to tachycardia. Studies in cholesterol-fed rats (7 d treatment) showed that GC-1 reduced cholesterol (ED50 = 190 nmol/kg·d) approximately 30 times more potently than it induced tachycardia (ED15 = 5451 nmol/ kg·d). T3 showed no potency difference between cholesterol lowering and tachycardia. GC-1 showed approximately 10-fold selectivity for increasing metabolic rate (ED5 = 477 nmol/ kg·d) relative to tachycardia compared with T3, which showed no selectivity. In cynomolgus monkeys treated for 7 d, significant cholesterol-lowering and lipoprotein (a) reduction was noted for both T 3 and GC-1, whereas no tachycardia was observed for GC-1, unlike T3. T3 and GC-1 caused a significant (∼4{\%}) reduction in body weight in these animals. Therefore, selective TRβ activation may be a potentially usefully treatment for obesity and reduction of low density lipoprotein cholesterol and reduction of the atherogenic risk factor lipoprotein (a).",
author = "Grover, {Gary J.} and Egan, {Donald M.} and Sleph, {Paul G.} and Beehler, {Blake C.} and Grazia Chiellini and Nguyen, {Ngoc Ha} and Baxter, {John D.} and Scanlan, {Thomas (Tom)}",
year = "2004",
month = "4",
doi = "10.1210/en.2003-0973",
language = "English (US)",
volume = "145",
pages = "1656--1661",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "4",

}

TY - JOUR

T1 - Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates

T2 - Selective actions relative to 3,5,3′-triiodo-L-thyronine

AU - Grover, Gary J.

AU - Egan, Donald M.

AU - Sleph, Paul G.

AU - Beehler, Blake C.

AU - Chiellini, Grazia

AU - Nguyen, Ngoc Ha

AU - Baxter, John D.

AU - Scanlan, Thomas (Tom)

PY - 2004/4

Y1 - 2004/4

N2 - Current drug therapies for obesity are ineffective, and existing treatments for lipid disorders can be further improved. Thyroid hormones affect both conditions, although currently available nonselective thyromimetics are not clinically useful for such treatment due to cardiac side effects. Recent studies suggest that thyroid hormone receptor subtype β(TRβ) selective agonists have a profile in which cholesterol can be reduced with minimal tachycardia. The purpose of this study was to determine whether modest (5-10%) increases in metabolic rate could also be observed with minimal tachycardia after TRβ stimulation. For these studies, the TRβ selective agonist, GC-1, was used to assess selectivity for lipid-lowering and metabolic rate changes relative to tachycardia. Studies in cholesterol-fed rats (7 d treatment) showed that GC-1 reduced cholesterol (ED50 = 190 nmol/kg·d) approximately 30 times more potently than it induced tachycardia (ED15 = 5451 nmol/ kg·d). T3 showed no potency difference between cholesterol lowering and tachycardia. GC-1 showed approximately 10-fold selectivity for increasing metabolic rate (ED5 = 477 nmol/ kg·d) relative to tachycardia compared with T3, which showed no selectivity. In cynomolgus monkeys treated for 7 d, significant cholesterol-lowering and lipoprotein (a) reduction was noted for both T 3 and GC-1, whereas no tachycardia was observed for GC-1, unlike T3. T3 and GC-1 caused a significant (∼4%) reduction in body weight in these animals. Therefore, selective TRβ activation may be a potentially usefully treatment for obesity and reduction of low density lipoprotein cholesterol and reduction of the atherogenic risk factor lipoprotein (a).

AB - Current drug therapies for obesity are ineffective, and existing treatments for lipid disorders can be further improved. Thyroid hormones affect both conditions, although currently available nonselective thyromimetics are not clinically useful for such treatment due to cardiac side effects. Recent studies suggest that thyroid hormone receptor subtype β(TRβ) selective agonists have a profile in which cholesterol can be reduced with minimal tachycardia. The purpose of this study was to determine whether modest (5-10%) increases in metabolic rate could also be observed with minimal tachycardia after TRβ stimulation. For these studies, the TRβ selective agonist, GC-1, was used to assess selectivity for lipid-lowering and metabolic rate changes relative to tachycardia. Studies in cholesterol-fed rats (7 d treatment) showed that GC-1 reduced cholesterol (ED50 = 190 nmol/kg·d) approximately 30 times more potently than it induced tachycardia (ED15 = 5451 nmol/ kg·d). T3 showed no potency difference between cholesterol lowering and tachycardia. GC-1 showed approximately 10-fold selectivity for increasing metabolic rate (ED5 = 477 nmol/ kg·d) relative to tachycardia compared with T3, which showed no selectivity. In cynomolgus monkeys treated for 7 d, significant cholesterol-lowering and lipoprotein (a) reduction was noted for both T 3 and GC-1, whereas no tachycardia was observed for GC-1, unlike T3. T3 and GC-1 caused a significant (∼4%) reduction in body weight in these animals. Therefore, selective TRβ activation may be a potentially usefully treatment for obesity and reduction of low density lipoprotein cholesterol and reduction of the atherogenic risk factor lipoprotein (a).

UR - http://www.scopus.com/inward/record.url?scp=1642505721&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1642505721&partnerID=8YFLogxK

U2 - 10.1210/en.2003-0973

DO - 10.1210/en.2003-0973

M3 - Article

C2 - 14701670

AN - SCOPUS:1642505721

VL - 145

SP - 1656

EP - 1661

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 4

ER -