APPL1 knockdown blocks adipogenic differentiation and promotes adipocyte lipolysis
APPL1 knockdown blocks adipogenic differentiation and promotes adipocyte lipolysis
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APPL1 敲低阻止脂肪形成分化并促进脂肪细胞脂肪分解
DOI：
10.1016/j.mce.2020.110755
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发表时间：
2020-02
影响因子：
4.1
通讯作者：
Changhua Wang
中科院分区：
文献类型：
--
作者：
Zhongyuan Wen;Zhao Tang;Mingxin Li;Yemin Zhang;Junfeng Li;Yingkang Cao;Deling Zhang;Yalin Fu;Changhua Wang
脂肪细胞功能障碍与肥胖、胰岛素抵抗和2型糖尿病的发展密切相关。除了通过直接和/或间接机制对脂联素途径和胰岛素信号传导具有积极作用外，还报道了衔接蛋白APPL 1在糖尿病个体中调节体重、棕色脂肪组织产热和体脂分布。然而，关于APPL 1在脂肪形成分化和脂肪细胞脂解中的具体作用的数据缺乏。本研究旨在探讨APPL 1在脂肪细胞分化和脂肪分解中的作用，并探讨其可能的机制。我们发现APPL 1敲低（KD）阻碍了3 T3-L1前脂肪细胞向成熟3 T3-L1脂肪细胞的分化，并增强了成熟3 T3-L1脂肪细胞中的基础和胰岛素抑制的脂解。APPL 1 KD细胞在3 T3-L1前脂肪细胞和成熟3 T3-L1脂肪细胞中呈现降低的自噬活性。在3 T3-L1前脂肪细胞中，APPL 1 KD降低了PPARγ蛋白水平，这可通过给予蛋白酶体抑制剂MG 132来阻止。此外，APPL 1 KD减少的自噬活性在成熟的3 T3-L1脂肪细胞显着恢复PKA的抑制，伴随着APPL 1诱导的脂解的预防。此外，APPL 1 KD在成熟的3 T3-L1脂肪细胞中引起胰岛素抵抗。出乎意料的是，我们发现APPL 1过表达似乎在脂肪形成分化和脂肪细胞脂解中不起作用。我们的研究结果证实APPL 1 KD通过抑制自噬抑制脂肪细胞分化，通过激活PKA促进脂肪细胞脂解。这些发现可能加深我们对APPL 1功能的理解，特别是其对脂肪细胞生物学的调控。
Adipocyte dysfunction is closely associated with the development of obesity, insulin resistance, and type 2 diabetes. In addition to having a positive effect on adiponectin pathway and insulin signaling through direct and/or indirect mechanisms, adapter protein APPL1 has also been reported to regulate body weight, brown fat tissues thermogenesis, and body fat distribution in diabetic individuals. However, there is dearth of data on the specific role of APPL1 on adipogenic differentiation and adipocyte lipolysis. In this study, APPL1's function in adipocyte differentiation and adipocyte lipolysis was evaluated, and the possible mechanisms were investigated. We found that APPL1 knockdown (KD) impeded differentiation of 3T3-L1 preadipocytes into mature 3T3-L1 adipocytes and enhanced basal and insulin-suppressed lipolysis in mature 3T3-L1 adipocytes. APPL1 KD cells presented a reduced autophagic activity in 3T3-L1 preadipocytes and mature 3T3-L1 adipocytes. In 3T3-L1 preadipocytes, APPL1 KD reduced PPARγ protein levels, which was prevented by administration with proteasome inhibitor MG132. Furthermore, APPL1 KD-reduced autophagic activity in mature 3T3-L1 adipocytes was markedly restored by inhibition of PKA, accompanied with prevention of APPL1-induced lipolysis. In addition, APPL1 KD caused insulin resistance in mature 3T3-L1 adipocytes. Unexpectedly, we found that APPL1 overexpression did not appear to play a role in adipogenic differentiation and adipocyte lipolysis. Our results confirmed that APPL1 KD inhibits adipogenic differentiation by suppressing autophagy and enhances adipocyte lipolysis through activating PKA respectively. These findings may deepen our understanding of APPL1 function, especially its regulation on adipocyte biology.
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影响因子：
6.5
作者：
P. Björntorp;M. Karlsson;P. Pettersson;G. Sypniewska
通讯作者：
P. Björntorp;M. Karlsson;P. Pettersson;G. Sypniewska
影响因子：
3.9
作者：
Diggins NL;Webb DJ
通讯作者：
Webb DJ
影响因子：
5.6
作者：
Li M;Zhang Y;Cao Y;Zhang D;Liu L;Guo Y;Wang C
通讯作者：
Wang C
影响因子：
3.7
作者：
Ishida M;Shimabukuro M;Yagi S;Nishimoto S;Kozuka C;Fukuda D;Soeki T;Masuzaki H;Tsutsui M;Sata M
通讯作者：
Sata M
影响因子：
5.6
作者：
Yoshii SR;Mizushima N
通讯作者：
Mizushima N