Rheb Inhibits Beigeing of White Adipose Tissue via PDE4D5-dependent Down-regulation of the cAMP-PKA Signaling Pathway
Rheb Inhibits Beigeing of White Adipose Tissue via PDE4D5-dependent Down-regulation of the cAMP-PKA Signaling Pathway
复制标题
Rheb 通过 PDE4D5 依赖性下调 cAMP-PKA 信号通路抑制白色脂肪组织米色变
作者：
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
米色白色脂肪组织具有潜在的抗肥胖和抗糖尿病作用，但潜在的信号机制仍有待充分阐明。在这里，我们证明，mTORC1 上游激活剂 Rheb 的脂肪特异性敲除可以保护小鼠免受高脂肪饮食引起的肥胖和胰岛素抵抗。脂肪组织中的 Rheb 缺乏会减少 mTORC1 信号传导，增加脂肪分解，并促进米色和能量消耗。另一方面，原代脂肪细胞中Rheb的过度表达显着抑制CREB磷酸化和UCP1表达。从机制上讲，脂肪特异性敲除 Rheb 增加了皮下白色脂肪组织中的 cAMP 水平、PKA 活性和 UCP1 表达。有趣的是，用雷帕霉素处理原代脂肪细胞仅部分减轻了Rheb对UCP1表达的抑制作用，这表明Rheb对产热基因表达的抑制作用存在一种新的机制。与这一观点一致，Rheb 的过表达稳定了脂肪细胞中 cAMP 特异性磷酸二酯酶-4D5 的表达，而 Rheb 的敲除大大降低了磷酸二酯酶-4D5 的细胞水平，同时 cAMP 水平、PKA 激活和 UCP1 表达增加。综上所述，我们的研究结果表明 Rheb 是米色脂肪发育和生热作用的重要负调节因子。此外，Rheb 能够通过独立于 mTORC1 的机制抑制米色效应
Beigeing of white adipose tissue has potential anti-obesity and anti-diabetes effects, yet the underlying signaling mechanisms remain to be fully elucidated. Here we show that adipose-specific knockout of Rheb, an upstream activator of mTORC1, protects mice from high fat diet-induced obesity and insulin resistance. Rheb deficiency in adipose tissue reduced mTORC1 signaling, increased lipolysis, and promoted beigeing and energy expenditure. On the other hand, overexpression of Rheb in primary adipocytes significantly inhibited CREB phosphorylation and UCP1 expression. Mechanistically, fat-specific knockout of Rheb increased cAMP levels, 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 in adipocytes, whereas knockout of Rheb greatly reduced cellular levels of phosphodiesterase-4D5, 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 beigeing effect through an mTORC1-independent mechanism