Alterations in the distribution and orexigenic effects of dexamethasone in CAR-null mice.
The constitutive androstane receptor (CAR, NR1I3) has emerged as an important regulator of drug metabolism. CAR responds to a wide spectrum of xenobiotics by inducing expression of cytochrome P450 (CYP) enzymes and a number of other proteins responsible for drug metabolism in the liver. The xenosensor function of CAR overlaps with that of the pregnane X receptor (PXR), another xenobiotic receptor that belongs to the nuclear hormone superfamily. We observed that injection of dexamethasone (Dex), a ligand for the glucocorticoid receptor (GR) and PXR but not CAR, results in an unexpected twofold increase in the stomach weight of CAR-null animals relative to wild-type animals. Here, we show that CAR knockout mice have elevated levels of Dex in the brain, resulting in a more rapid and robust increase in the hypothalamic expression of the GR-responsive target genes encoding neuropeptide Y (NPY) and neuropeptide Y receptor subtype 1 (NPY-R1). As expected, this is accompanied by a higher increase in the food intake of the CAR-null animals. The data described here highlight the complexity of the overlapping functions of CAR and PXR.
Qatanani
Mohammed
M
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Room N610, Houston, TX 77030, USA.
Wei
Ping
P
Moore
David D
DD
D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D000090702:Constitutive Androstane Receptor; D003907:Dexamethasone / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D017476:Receptors, Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics; D013270:Stomach / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*
D000090702:Constitutive Androstane Receptor; D009478:Neuropeptide Y; C000716328:Nr1i3 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D017476:Receptors, Neuropeptide Y; D014157:Transcription Factors; C097212:neuropeptide Y-Y1 receptor; D003907:Dexamethasone