Sustained activation of autophagy suppresses adipocyte maturation via a lipolysis-dependent mechanism.
Sustained activation of autophagy suppresses adipocyte maturation via a lipolysis-dependent mechanism.
复制标题
自噬的持续激活通过脂解依赖性机制抑制脂肪细胞成熟。
DOI：
10.1080/15548627.2019.1703355
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发表时间：
2020
期刊：
影响因子：
13.3
通讯作者：
Liu,Meilian
中科院分区：
文献类型：
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作者：
Zhang,Xing;Wu,Dandan;Wang,Chunqing;Luo,Yan;Ding,Xiaofeng;Yang,Xin;Silva,Floyd;Arenas,Sara;Weaver,JohnMichael;Mandell,Michael;Deretic,Vojo;Liu,Meilian
巨自噬/自噬的失调与肥胖和胰岛素抵抗有关。然而，自噬如何调节脂肪细胞发育仍不清楚。使用脂肪特异性rptor/raptor敲除（KO）、atg7KO和atg7 rptordouble-KO小鼠，我们发现通过RPTOR缺陷抑制MTORC1会导致脂滴的自噬隔离，含有LD的溶酶体的形成，以及体内和原代脂肪细胞中基础和异丙肾上腺素诱导的脂解作用的升高。尽管早期分化正常，但在rptorKO脂肪细胞的终末分化过程中，细胞LD逐渐降解和收缩，脂肪形成标志物PPARG和PLIN1下调，这可以通过抑制脂解或溶酶体来挽救。相反，在体外，通过消耗 ATG7 来灭活自噬可以保护脂肪细胞免受 RPTOR 缺陷诱导的含 LD 的溶酶体的形成、LD 降解和脂肪形成标记物的下调。最终，与 RPTOR 缺陷小鼠相比，atg7 rptordouble-KO 小鼠在体内表现出脂肪分解减少、脂肪组织发育恢复、棕色和腹股沟脂肪组织中生热基因表达上调。总的来说，我们的研究表明自噬通过脂肪自噬和脂肪分解依赖性机制在调节脂肪细胞成熟中发挥重要作用。缩写ATG7：自噬相关7； BAT：棕色脂肪组织； CEBPB/C/EBPβ：CCAAT增强子结合蛋白β； DGAT1：二酰基甘油O-酰基转移酶1； eWAT：附睾白色脂肪组织； iWAT：腹股沟白色脂肪组织； KO：淘汰赛； LD：脂滴； MAP1LC3/LC3：微管相关蛋白1轻链3； MTOR：雷帕霉素激酶的机制靶点； MTORC1：雷帕霉素激酶复合物 1 的机制靶点； PLIN1：perepilin 1； PNPLA2/ATGL：含2个patatin样磷脂酶结构域； PPARG/PPARγ：过氧化物酶体增殖物激活受体γ； RPTOR：MTOR复合体1的调节相关蛋白； TG：甘油三酯； ULK1：unc-51 样激酶 1； UCP1：解偶联蛋白1； WAT：白色脂肪组织
Dysregulation of macroautophagy/autophagy is implicated in obesity and insulin resistance. However, it remains poorly defined how autophagy regulates adipocyte development. Using adipose-specificrptor/raptorknockout (KO),atg7KO andatg7 rptordouble-KO mice, we show that inhibiting MTORC1 by RPTOR deficiency led to autophagic sequestration of lipid droplets, formation of LD-containing lysosomes, and elevation of basal and isoproterenol-induced lipolysisin vivoand in primary adipocytes. Despite normal differentiation at an early phase, progressive degradation and shrinkage of cellular LDs and downregulation of adipogenic markers PPARG and PLIN1 occurred in terminal differentiation ofrptorKO adipocytes, which was rescued by inhibiting lipolysis or lysosome. In contrast, inactivating autophagy by depletion of ATG7 protected adipocytes against RPTOR deficiency-induced formation of LD-containing lysosomes, LD degradation, and downregulation of adipogenic markersin vitro. Ultimately,atg7 rptordouble-KO mice displayed decreased lipolysis, restored adipose tissue development, and upregulated thermogenic gene expression in brown and inguinal adipose tissue compared to RPTOR-deficient micein vivo. Collectively, our study demonstrates that autophagy plays an important role in regulating adipocyte maturation via a lipophagy and lipolysis-dependent mechanism.AbbreviationsATG7: autophagy related 7; BAT: brown adipose tissue; CEBPB/C/EBPβ: CCAAT enhancer binding protein beta; DGAT1: diacylglycerol O-acyltransferase 1; eWAT: epididymal white adipose tissue; iWAT: inguinal white adipose tissue; KO: knockout; LD: lipid droplet; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; PLIN1: perepilin 1; PNPLA2/ATGL: patatin-like phospholipase domain containing 2; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; RPTOR: regulatory associated protein of MTOR complex1; TG: triglyceride; ULK1: unc-51 like kinase 1; UCP1: uncoupling protein 1; WAT: white adipose tissue