Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice.
Obesity is a complex metabolic disorder that is more prevalent among women. Until now, the only relevant rodent models of diet-induced obesity were via the use of ovariectomized ("postmenopausal") females. However, recent reports suggest that the xenobiotic nuclear receptor pregnane X receptor (PXR) may contribute to obesity. Therefore, we compared the roles of mouse and human PXRs in diet-induced obesity between wild type (WT) and PXR-humanized (hPXR) transgenic female mice fed either control or high-fat diets (HFD) for 16 weeks. HFD-fed hPXR mice gained weight more rapidly than controls, exhibited hyperinsulinemia, and impaired glucose tolerance. Fundamental differences were observed between control-fed hPXR and WT females: hPXR mice possessed reduced estrogen receptor α (ERα) but enhanced uncoupling protein 1 (UCP1) protein expression in white adipose tissue (WAT); increased protein expression of the hepatic cytochrome P450 3A11 (CYP3A11) and key gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, and increased total cholesterol. Interestingly, HFD ingestion induced both UCP1 and glucokinase protein expression in WT mice, but inhibited these enzymes in hPXR females. Unlike WT mice, CYP3A11 protein, serum 17β-estradiol levels, and WAT ERα expression were unaffected by HFD in hPXR females. Together, these studies indicate that the hPXR gene promotes obesity and metabolic syndrome by dysregulating lipid and glucose homeostasis while inhibiting UCP1 expression. Furthermore, our studies indicate that the human PXR suppresses the protective role of estrogen in metabolic disorders. Finally, these data identify PXR-humanized mice as a promising in vivo research model for studying obesity and diabetes in women.
Cardiovascular & Metabolic Diseases Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George St., Durham, NC 27707, USA; Department of Biology, North Carolina Central University, Durham, NC 27707, USA.
Krisstonia
K
Spruiell
Cardiovascular & Metabolic Diseases Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George St., Durham, NC 27707, USA.
Dominique Z
DZ
Jones
North Carolina College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA.
John M
JM
Cullen
Cardiovascular & Metabolic Diseases Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George St., Durham, NC 27707, USA; Department of Biology, North Carolina Central University, Durham, NC 27707, USA.
Emmanuel M
EM
Awumey
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Building 37, Room 3106, Bethesda, MD 20892, USA.
Frank J
FJ
Gonzalez
Cardiovascular & Metabolic Diseases Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George St., Durham, NC 27707, USA. Electronic address: mgyamfi@nccu.edu.
Maxwell A
MA
Gyamfi
D052436:Adipose Tissue, White; D000818:Animals; D001786:Blood Glucose; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D005260:Female; D005786:Gene Expression Regulation; D018149:Glucose Intolerance; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008099:Liver; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D000071256:Uncoupling Protein 1
D001786:Blood Glucose; D004041:Dietary Fats; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A
Females; High-fat diet; Nuclear receptors; Obesity; Pregnane X receptor; Type 2 diabetes