Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway.
Rheb Inhibits Beiging of White Adipose Tissue via PDE4D5-Dependent Downregulation of the cAMP-PKA Signaling Pathway.
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作者：
Meng W;Liang X;Chen H;Luo H;Bai J;Li G;Zhang Q;Xiao T;He S;Zhang Y;Xu Z;Xiao B;Liu M;Hu F;Liu F
米色白色脂肪组织具有潜在的抗肥胖和抗糖尿病作用，但其潜在的信号机制仍未完全阐明。在这里，我们展示了Rheb的脂肪特异性敲除，Rheb是雷帕霉素复合体1(MTORC1)机械靶点的上游激活剂，可以保护小鼠免受高脂饮食诱导的肥胖和胰岛素抵抗。一方面，脂肪组织中Rheb缺乏减少了mTORC1信号，增加了脂肪分解，促进了褐变和能量消耗。另一方面，Rheb在原代脂肪细胞中的过表达显著抑制CREB的磷酸化和解偶联蛋白1(UCP1)的表达。从机制上讲，脂肪特异的Rheb基因敲除增加了皮下白色脂肪组织中cAMP水平、cAMP依赖蛋白激酶(PKA)活性和UCP1表达。有趣的是，用雷帕霉素处理原代脂肪细胞只能部分缓解Rheb对UCP1表达的抑制作用，这表明Rheb抑制生热基因表达存在新的机制。与这一观点一致，Rheb的过表达稳定了脂肪细胞中cAMP特异性的磷酸二酯酶4D5(PDE4D5)的表达，而Rheb的敲除显著降低了细胞中PDE4D5的水平，同时增加了cAMP水平、PKA激活和UCP1的表达。综上所述，我们的发现揭示了Rheb是米色脂肪发育和产热的重要负调控因子。此外，Rheb能够通过不依赖mTORC1的机制抑制褐变效应。
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.
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影响因子：
4.3
作者：
Cinti S
通讯作者：
Cinti S
影响因子：
9.2
作者：
Long, X;Lin, Y;Avruch, J
通讯作者：
Avruch, J
影响因子：
4.8
作者：
Cao, WH;Medvedev, AV;Collins, S
通讯作者：
Collins, S
DOI：
10.1006/bbrc.2001.5874
发表时间：
2001-11-09
影响因子：
3.1
作者：
Fasshauer, M;Klein, J;Paschke, R
通讯作者：
Paschke, R
糖皮质激素转录调节 miR-27b 表达通过抑制白色脂肪组织褐变促进体内脂肪积累
影响因子：
7.7
作者：
Kong X;Yu J;Bi J;Qi H;Di W;Wu L;Wang L;Zha J;Lv S;Zhang F;Li Y;Hu F;Liu F;Zhou H;Liu J;Ding G
通讯作者：
Ding G