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J. Biol. Chem., Vol. 279, Issue 19, 19832-19838, May 7, 2004

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The Nuclear Receptor CAR Is a Regulator of Thyroid Hormone Metabolism during Caloric Restriction^*

Jodi M. Maglich, Joe Watson, Patrick J. McMillen¶, Bryan Goodwin, Timothy M. Willson||, and John T. Moore**

From the High Throughput Biology, Bioscience Support, ^¶Genetics Research, and ^||High Throughput Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709

The orphan nuclear receptor CAR (NR1I3) has been characterized as a central component in the coordinate response to xenobiotic and endobiotic stress. In this study, we demonstrate that CAR plays a pivotal function in energy homeostasis and establish an unanticipated metabolic role for this nuclear receptor. Wild-type mice treated with the synthetic CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) exhibited decreased serum concentration of the thyroid hormone (TH) thyroxine (T₄). However, treatment of Car^–/– mice with TCPOBOP failed to elicit these changes. To examine whether CAR played a role in the regulation of TH levels under physiological conditions, wild-type and Car^–/– mice were fasted for 24 h, a process known to alter TH metabolism in mammals. As expected, the serum triiodothyronine and T₄ concentrations decreased in wild-type mice. However, triiodothyronine and T₄ levels in fasted Car^–/– mice remained significantly higher than those in fasted wild-type animals. Concomitant with the changes in serum TH levels, both CAR agonist treatment and fasting induced the expression of CAR target genes (notably, Cyp2b10, Ugt1a1, Sultn, Sult1a1, and Sult2a1) in a receptor-dependent manner. Importantly, the Ugt1a1, Sultn, Sult1a1, and Sult2a1 genes encode enzymes that are capable of metabolizing TH. An attenuated reduction in TH levels during fasting, as observed in Car^–/– mice, would be predicted to increase weight loss during caloric restriction. Indeed, when Car^–/– animals were placed on a 40% caloric restriction diet for 12 weeks, Car^–/– animals lost over twice as much weight as their wild-type littermates. Thus, CAR participates in the molecular mechanisms contributing to homeostatic resistance to weight loss. These data imply that CAR represents a novel therapeutic target to uncouple metabolic rate from food intake and has implications in obesity and its associated disorders.

Received for publication, December 11, 2003 , and in revised form, February 27, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: GlaxoSmithKline, 5 Moore Dr., Venture116-1b, Research Triangle Park, NC 27709. Tel.: 919-483-3936; Fax: 919-315-6720; E-mail: John.T.Moore{at}gsk.com.

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