Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR)
Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic diseases. Activation of constitutive androstane receptor (CAR), a xenobiotic-sensing nuclear receptor, has been shown to inhibit obesity,...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-02-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383520306997 |
| _version_ | 1811271175983071232 |
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| author | Xinran Cai Ye Feng Meishu Xu Chaohui Yu Wen Xie |
| author_facet | Xinran Cai Ye Feng Meishu Xu Chaohui Yu Wen Xie |
| author_sort | Xinran Cai |
| collection | DOAJ |
| description | Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic diseases. Activation of constitutive androstane receptor (CAR), a xenobiotic-sensing nuclear receptor, has been shown to inhibit obesity, suppress hepatic gluconeogenesis, and ameliorate hyperglycemia in rodent models of obesity and type 2 diabetes. However, the underlying molecular mechanism remains to be defined. The growth arrest and DNA damage-inducible gene 45b (Gadd45b), a well-known anti-apoptotic factor, has been shown to be an inducible coactivator of CAR in promoting rapid liver growth. It is unknown whether the effect of CAR on energy metabolism depends on GADD45B. In the present study and by using a high fat diet (HFD)-induced obesity model, we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) were markedly blunted in Gadd45b knockout mice. Mechanistically, the TCPOBOP-responsive inhibition of hepatic lipogenesis, gluconeogenesis, and adipose inflammation observed in wild type mice were largely abolished in Gadd45b knockout mice. We conclude that Gadd45b is required in part for the metabolic benefits of CAR activation. |
| first_indexed | 2024-04-12T22:16:37Z |
| format | Article |
| id | doaj.art-9f07722dbdf047fd98818a9255852684 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-04-12T22:16:37Z |
| publishDate | 2021-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-9f07722dbdf047fd98818a92558526842022-12-22T03:14:32ZengElsevierActa Pharmaceutica Sinica B2211-38352021-02-01112434441Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR)Xinran Cai0Ye Feng1Meishu Xu2Chaohui Yu3Wen Xie4Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USACenter for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Endocrinology and Metabolic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, ChinaCenter for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USADepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Corresponding authors.Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA; Corresponding authors.Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic diseases. Activation of constitutive androstane receptor (CAR), a xenobiotic-sensing nuclear receptor, has been shown to inhibit obesity, suppress hepatic gluconeogenesis, and ameliorate hyperglycemia in rodent models of obesity and type 2 diabetes. However, the underlying molecular mechanism remains to be defined. The growth arrest and DNA damage-inducible gene 45b (Gadd45b), a well-known anti-apoptotic factor, has been shown to be an inducible coactivator of CAR in promoting rapid liver growth. It is unknown whether the effect of CAR on energy metabolism depends on GADD45B. In the present study and by using a high fat diet (HFD)-induced obesity model, we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) were markedly blunted in Gadd45b knockout mice. Mechanistically, the TCPOBOP-responsive inhibition of hepatic lipogenesis, gluconeogenesis, and adipose inflammation observed in wild type mice were largely abolished in Gadd45b knockout mice. We conclude that Gadd45b is required in part for the metabolic benefits of CAR activation.http://www.sciencedirect.com/science/article/pii/S2211383520306997ObesityDiabetesCARGadd45bGlucogenogenesisLipogenesis |
| spellingShingle | Xinran Cai Ye Feng Meishu Xu Chaohui Yu Wen Xie Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR) Acta Pharmaceutica Sinica B Obesity Diabetes CAR Gadd45b Glucogenogenesis Lipogenesis |
| title | Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR) |
| title_full | Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR) |
| title_fullStr | Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR) |
| title_full_unstemmed | Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR) |
| title_short | Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR) |
| title_sort | gadd45b is required in part for the anti obesity effect of constitutive androstane receptor car |
| topic | Obesity Diabetes CAR Gadd45b Glucogenogenesis Lipogenesis |
| url | http://www.sciencedirect.com/science/article/pii/S2211383520306997 |
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