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 ofCar–/–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 andCar–/–mice were fasted for 24 h, a process known to alter TH metabolism in mammals. As expected, the serum triiodothyronine and T4concentrations decreased in wild-type mice. However, triiodothyronine and T4levels in fastedCar–/–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, andSult2a1) in a receptor-dependent manner. Importantly, theUgt1a1, Sultn, Sult1a1, andSult2a1genes encode enzymes that are capable of metabolizing TH. An attenuated reduction in TH levels during fasting, as observed inCar–/–mice, would be predicted to increase weight loss during caloric restriction. Indeed, whenCar–/–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.
The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury
