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Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway
Beiging of white adipose tissue has potential antiobesity and antidiabetes effects, yet the underlying signaling mechanisms remain to be fully elucidated. Here we show that adipose-specific knockout of Rheb, an upstream activator of mechanistic target of rapamycin complex 1 (mTORC1), protects mice f...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860267/ https://www.ncbi.nlm.nih.gov/pubmed/28242620 http://dx.doi.org/10.2337/db16-0886 |
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author | Meng, Wen Liang, Xiuci Chen, Hongzhi Luo, Hairong Bai, Juli Li, Guangdi Zhang, Qinghai Xiao, Ting He, Sijia Zhang, Yacheng Xu, Zhipeng Xiao, Bo Liu, Meilian Hu, Fang Liu, Feng |
author_facet | Meng, Wen Liang, Xiuci Chen, Hongzhi Luo, Hairong Bai, Juli Li, Guangdi Zhang, Qinghai Xiao, Ting He, Sijia Zhang, Yacheng Xu, Zhipeng Xiao, Bo Liu, Meilian Hu, Fang Liu, Feng |
author_sort | Meng, Wen |
collection | PubMed |
description | Beiging of white adipose tissue has potential antiobesity and antidiabetes effects, yet the underlying signaling mechanisms remain to be fully elucidated. Here we show that adipose-specific knockout of Rheb, an upstream activator of mechanistic target of rapamycin complex 1 (mTORC1), protects mice from high-fat diet–induced obesity and insulin resistance. On the one hand, Rheb deficiency in adipose tissue reduced mTORC1 signaling, increased lipolysis, and promoted beiging and energy expenditure. On the other hand, overexpression of Rheb in primary adipocytes significantly inhibited CREB phosphorylation and uncoupling protein 1 (UCP1) expression. Mechanistically, fat-specific knockout of Rheb increased cAMP levels, cAMP-dependent protein kinase (PKA) activity, and UCP1 expression in subcutaneous white adipose tissue. Interestingly, treating primary adipocytes with rapamycin only partially alleviated the suppressing effect of Rheb on UCP1 expression, suggesting the presence of a novel mechanism underlying the inhibitory effect of Rheb on thermogenic gene expression. Consistent with this notion, overexpression of Rheb stabilizes the expression of cAMP-specific phosphodiesterase 4D5 (PDE4D5) in adipocytes, whereas knockout of Rheb greatly reduced cellular levels of PDE4D5 concurrently with increased cAMP levels, PKA activation, and UCP1 expression. Taken together, our findings reveal Rheb as an important negative regulator of beige fat development and thermogenesis. In addition, Rheb is able to suppress the beiging effect through an mTORC1-independent mechanism. |
format | Online Article Text |
id | pubmed-5860267 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-58602672018-05-01 Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway Meng, Wen Liang, Xiuci Chen, Hongzhi Luo, Hairong Bai, Juli Li, Guangdi Zhang, Qinghai Xiao, Ting He, Sijia Zhang, Yacheng Xu, Zhipeng Xiao, Bo Liu, Meilian Hu, Fang Liu, Feng Diabetes Obesity Studies Beiging of white adipose tissue has potential antiobesity and antidiabetes effects, yet the underlying signaling mechanisms remain to be fully elucidated. Here we show that adipose-specific knockout of Rheb, an upstream activator of mechanistic target of rapamycin complex 1 (mTORC1), protects mice from high-fat diet–induced obesity and insulin resistance. On the one hand, Rheb deficiency in adipose tissue reduced mTORC1 signaling, increased lipolysis, and promoted beiging and energy expenditure. On the other hand, overexpression of Rheb in primary adipocytes significantly inhibited CREB phosphorylation and uncoupling protein 1 (UCP1) expression. Mechanistically, fat-specific knockout of Rheb increased cAMP levels, cAMP-dependent protein kinase (PKA) activity, and UCP1 expression in subcutaneous white adipose tissue. Interestingly, treating primary adipocytes with rapamycin only partially alleviated the suppressing effect of Rheb on UCP1 expression, suggesting the presence of a novel mechanism underlying the inhibitory effect of Rheb on thermogenic gene expression. Consistent with this notion, overexpression of Rheb stabilizes the expression of cAMP-specific phosphodiesterase 4D5 (PDE4D5) in adipocytes, whereas knockout of Rheb greatly reduced cellular levels of PDE4D5 concurrently with increased cAMP levels, PKA activation, and UCP1 expression. Taken together, our findings reveal Rheb as an important negative regulator of beige fat development and thermogenesis. In addition, Rheb is able to suppress the beiging effect through an mTORC1-independent mechanism. American Diabetes Association 2017-05 2017-02-27 /pmc/articles/PMC5860267/ /pubmed/28242620 http://dx.doi.org/10.2337/db16-0886 Text en © 2017 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. |
spellingShingle | Obesity Studies Meng, Wen Liang, Xiuci Chen, Hongzhi Luo, Hairong Bai, Juli Li, Guangdi Zhang, Qinghai Xiao, Ting He, Sijia Zhang, Yacheng Xu, Zhipeng Xiao, Bo Liu, Meilian Hu, Fang Liu, Feng Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway |
title | Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway |
title_full | Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway |
title_fullStr | Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway |
title_full_unstemmed | Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway |
title_short | Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway |
title_sort | rheb inhibits beiging of white adipose tissue via pde4d5-dependent downregulation of the camp-pka signaling pathway |
topic | Obesity Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860267/ https://www.ncbi.nlm.nih.gov/pubmed/28242620 http://dx.doi.org/10.2337/db16-0886 |
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