Rheb inhibits beiging of white adipose tissue via PDE4D5-dependent downregulation of the cAMP-PKA signaling pathway

Wen Meng, Xiuci Liang, Hongzhi Chen, Hairong Luo, Juli Bai, Guangdi Li, Qinghai Zhang, Ting Xiao, Sijia He, Yacheng Zhang, Zhipeng Xu, Bo Xiao, Meilian Liu, Fang Hu, Feng Liu

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1198-1213
Number of pages16
JournalDiabetes
Volume66
Issue number5
DOIs
StatePublished - May 1 2017

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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