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Alterations in the distribution and orexigenic effects of dexamethasone in CAR-null mice
Mohammed Qatanani1, Ping Wei, David D Moore
1Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Room N610, Houston, TX 77030, USA.
Abstract:
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.
Insights
Constitutive androstane receptor (CAR) knockout mice show increased stomach weight and food intake after dexamethasone treatment. This is due to elevated brain drug levels and enhanced hypothalamic neuropeptide Y signaling.
Area of Science:
- Pharmacology
- Neuroendocrinology
- Molecular Biology
Background:
- The constitutive androstane receptor (CAR) regulates drug metabolism by inducing drug-metabolizing enzymes.
- CAR's function as a xenosensor overlaps with the pregnane X receptor (PXR).
- Dexamethasone (Dex), a ligand for glucocorticoid receptor (GR) and PXR, unexpectedly increased stomach weight in CAR-null mice.
Purpose of the Study:
- To investigate the role of CAR in mediating dexamethasone-induced physiological changes.
- To explore the interaction between CAR, GR, and PXR signaling pathways.
- To understand the neuroendocrine mechanisms underlying altered food intake in CAR-null animals.
Main Methods:
- Utilized CAR knockout (CAR-null) and wild-type mice.
- Administered dexamethasone (Dex) to assess physiological and molecular responses.
- Measured stomach weight, brain drug levels, and hypothalamic gene expression (NPY, NPY-R1).
Main Results:
- CAR-null mice exhibited a twofold increase in stomach weight compared to wild-type mice after Dex injection.
- Elevated Dex levels were observed in the brains of CAR-null animals.
- CAR deficiency led to enhanced hypothalamic expression of GR-responsive genes (NPY, NPY-R1) and increased food intake.
Conclusions:
- CAR plays a crucial role in modulating brain drug levels and associated neuroendocrine responses.
- The findings reveal a complex interplay between CAR, PXR, and GR signaling in regulating metabolism and behavior.
- CAR influences appetite regulation through its impact on hypothalamic neuropeptide signaling.
