Dataset Information

The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity.

ABSTRACT: Obesity and type 2 diabetes are related metabolic disorders of high prevalence. The constitutive androstane receptor (CAR) was initially characterized as a xenobiotic receptor regulating the responses of mammals to xenotoxicants. In this study, we have uncovered an unexpected role of CAR in preventing obesity and alleviating type 2 diabetes. Using a high fat diet (HFD)-induced obesity model, we showed that treatment of wild type mice with the CAR agonist 1,4-bis[2-(3,5 dichloropyridyloxy)] benzene (TCPOBOP) efficiently prevented obesity from happening or reversed preinduced obesity. Treatment with TCPOBOP improved insulin sensitivity in both the HFD-induced type 2 diabetic model and the ob/ob mice. In contrast, CAR null mice maintained on a chow diet showed spontaneous insulin insensitivity, which cannot be relieved by TOPOBOP treatment. The hepatic steatosis in HFD-treated mice and ob/ob mice was markedly reduced by the TCPOBOP treatment. The metabolic benefits of CAR activation may have resulted from the combined effect of inhibition of lipogenesis, very low density lipoprotein secretion and export of triglycerides, and gluconeogenesis as well as increases in brown adipose tissue energy expenditure and peripheral fat mobilization. Moreover, the skeletal muscle of CAR-activated mice showed a decreased incomplete oxidation, despite having a lower expression level of peroxisome proliferator-activated receptor alpha and its target genes involved in fatty acid oxidation. In summary, our results have revealed an important metabolic function of CAR and may establish this "xenobiotic receptor" as a novel therapeutic target for the prevention and treatment of obesity and type 2 diabetes.

SUBMITTER: Gao J

PROVIDER: S-EPMC2757999 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundEpidemiologic and genetic evidence links type 2 diabetes, obesity, and cancer. The tumor-suppressor phosphatase and tensin homologue (PTEN) has roles in both cellular growth and metabolic signaling. Germline PTEN mutations cause a cancer-predisposition syndrome, providing an opportunity to study the effect of PTEN haploinsufficiency in humans.MethodsWe measured insulin sensitivity and beta-cell function in 15 PTEN mutation carriers and 15 matched controls. Insulin signaling was measured in muscle and adipose-tissue biopsy specimens from 5 mutation carriers and 5 well-matched controls. We also assessed the effect of PTEN haploinsufficiency on obesity by comparing anthropometric indexes between the 15 patients and 2097 controls from a population-based study of healthy adults. Body composition was evaluated by means of dual-emission x-ray absorptiometry and skinfold thickness.ResultsMeasures of insulin resistance were lower in the patients with a PTEN mutation than in controls (e.g., mean fasting plasma insulin level, 29 pmol per liter [range, 9 to 99] vs. 74 pmol per liter [range, 22 to 185]; P=0.001). This finding was confirmed with the use of hyperinsulinemic euglycemic clamping, showing a glucose infusion rate among carriers 2 times that among controls (P=0.009). The patients' insulin sensitivity could be explained by the presence of enhanced insulin signaling through the PI3K-AKT pathway, as evidenced by increased AKT phosphorylation. The PTEN mutation carriers were obese as compared with population-based controls (mean body-mass index [the weight in kilograms divided by the square of the height in meters], 32 [range, 23 to 42] vs. 26 [range, 15 to 48]; P<0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution.ConclusionsPTEN haploinsufficiency is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic. We demonstrate an apparently divergent effect of PTEN mutations: increased risks of obesity and cancer but a decreased risk of type 2 diabetes owing to enhanced insulin sensitivity. (Funded by the Wellcome Trust and others.).

Project description:Chemotherapy is the most common treatment for cancer. However, multidrug resistance (MDR) remains a major obstacle to effective chemotherapy, limiting the efficacy of both conventional chemotherapeutic and novel biologic agents. The constitutive androstane receptor (CAR), a xenosensor, is a key regulator of MDR. It functions in xenobiotic detoxification by regulating the expression of phase I drug-metabolizing enzymes and ATP-binding cassette (ABC) transporters, whose overexpression in cancers and whose role in drug resistance make them potential therapeutic targets for reducing MDR. MicroRNAs (miRNAs) are endogenous negative regulators of gene expression and have been implicated in most cellular processes, including drug resistance. Here, we report the inversely related expression of miR-137 and CAR in parental and doxorubicin-resistant neuroblastoma cells, wherein miR-137 is downregulated in resistant cells. miR-137 overexpression resulted in downregulation of CAR protein and mRNA (via mRNA degradation); it sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis and increased G2-phase cell cycle arrest) and reduced the in vivo growth rate of neuroblastoma xenografts. We observed similar results in cellular models of hepatocellular and colon cancers, indicating that the doxorubicin-sensitizing effect of miR-137 is not tumor type-specific. Finally, we show for the first time a negative feedback loop whereby miR-137 downregulates CAR expression and CAR downregulates miR-137 expression. Hypermethylation of the miR-137 promoter and negative regulation of miR-137 by CAR contribute in part to reduced miR-137 expression and increased CAR and MDR1 expression in doxorubicin-resistant neuroblastoma cells. These findings demonstrate that miR-137 is a crucial regulator of cancer response to doxorubicin treatment, and they identify miR-137 as a highly promising target to reduce CAR-driven doxorubicin resistance.

Dataset Information

The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets