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 (T 4 ). 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 T 4 concentrations decreased in wild-type mice. However, triiodothyronine and T 4 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.In Western societies, obesity is reaching potentially epidemic proportions. In the United States, it is estimated that 55% of adults are overweight, and nearly a quarter are obese (1). Associated with the rise in obesity are concomitant rises in the incidence of metabolic syndrome or syndrome X, typified by type 2 diabetes, cardiovascular disease, hypertension, and hyperlipidemia. The epidemic of obesity inflicts significant disadvantages on both the individual and society, i.e. increased risk of death and disease, increased health care costs, and reduced social and educational status.A significant and discouraging factor for obese individuals trying to lose weight is that homeostatic resistance mechanisms operate to resist weight loss (2, 3). A major homeostatic barrier is decreased basal metabolic rate during periods of reduced caloric intake. Thyroid hormones (THs) 1 (thyroxine (T 4 ) and triiodothyronine (T 3 )) are the predominant regulators of basal metabolic rate. Serum levels of TH show a direct correlation with energy expenditure and caloric loss (4), decreasing significantly during fasting. The most potent...

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