Autophagy inhibition prevents glucocorticoid-increased adiposity via suppressing BAT whitening
Autophagy inhibition prevents glucocorticoid-increased adiposity via suppressing BAT whitening
复制标题
自噬抑制通过抑制 BAT 美白来防止糖皮质激素增加的肥胖
DOI：
10.1080/15548627.2019.1628537
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发表时间：
2019-06-20
期刊：
影响因子：
13.3
通讯作者：
Guo, Feifan
中科院分区：
文献类型：
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作者：
Deng, Jiali;Guo, Yajie;Guo, Feifan
摘要糖皮质激素（GC）增加肥胖的机制知之甚少。棕色脂肪组织（BAT）在某些情况下获得白色脂肪组织（WAT）细胞特征，其被定义为BAT变白。我们当前研究的目的是探讨GC诱导BAT美白的可能性和机制。在这里，我们表明，一周的地塞米松（Dex）治疗诱导BAT美白，其特征在于脂滴积累，在体外和体内。此外，自噬和ATG 7（自噬相关7）的表达诱导BAT的Dex，和治疗与自噬抑制剂氯喹或腺病毒介导的ATG 7敲低防止Dex诱导的BAT美白和脂肪量增加。此外，右旋糖酐增加的ATG 7表达和自噬是由BTG 1（B细胞易位基因1，抗增殖）的表达增强介导的，BTG 1刺激CREB 1（cAMP反应元件结合蛋白1）的活性。通过在脂肪细胞特异性BTG 1过表达小鼠中观察到的BAT变白以及在BAT中BTG 1敲低的小鼠中减弱的Dex诱导的BAT变白和脂肪量增加，进一步证明了BTG 1在该调节中的重要性。总之，我们发现Dex通过BTG 1和ATG 7依赖性自噬诱导BAT显着变白，这可能有助于Dex增加肥胖。这些结果为GC增加肥胖的潜在机制提供了新的见解，并通过联合使用自噬抑制剂预防GC诱导的副作用的可能策略。缩写ACADL：酰基辅酶A脱氢酶，长链; ACADM：酰基辅酶A脱氢酶，中链; ACADS：酰基辅酶A脱氢酶，短链; ADIPOQ：脂联素; AGT：血管紧张素原; Atg：自噬相关; BAT：棕色脂肪组织; BTG 1：B细胞易位基因1，抗增殖; CEBPA：CCAAT/增强子结合蛋白（C/EBP），α; CIDEA：细胞死亡诱导DNA片段化因子，α亚单位样效应子A; CPT 1B：肉毒碱棕榈酰转移酶1b，肌肉; CPT 2：肉毒碱棕榈酰转移酶2; CQ：氯喹; Dex：地塞米松; eWAT：附睾白色脂肪组织; FABP 4：脂肪酸结合蛋白4，脂肪细胞; FFA：游离脂肪酸;气相色谱：糖皮质激素类; NRIP 1：核受体相互作用蛋白1; OCR：氧消耗率; PBS：磷酸盐缓冲盐水; PPARA：过氧化物酶体增殖物激活受体α; PPARG：过氧化物酶体增殖物激活受体γ; PPARGC 1A：过氧化物酶体增殖物激活受体γ共激活因子1 α; PRDM 16：含有16的PR结构域; PSAT 1：磷酸丝氨酸氨基转移酶1; RB 1：RB转录辅阻遏物1; RBL 1/p107：RB转录辅阻遏物样1; SQSTM 1：螯合体1; sWAT：皮下白色脂肪组织; TG：甘油三酯; UCP 1：解偶联蛋白1（线粒体，质子载体）; WT：野生型
ABSTRACT The mechanisms underlying glucocorticoid (GC)-increased adiposity are poorly understood. Brown adipose tissue (BAT) acquires white adipose tissue (WAT) cell features defined as BAT whitening under certain circumstances. The aim of our current study was to investigate the possibility and mechanisms of GC-induced BAT whitening. Here, we showed that one-week dexamethasone (Dex) treatment induced BAT whitening, characterized by lipid droplet accumulation, in vitro and in vivo. Furthermore, autophagy and ATG7 (autophagy related 7) expression was induced in BAT by Dex, and treatment with the autophagy inhibitor chloroquine or adenovirus-mediated ATG7 knockdown prevented Dex-induced BAT whitening and fat mass gain. Moreover, Dex-increased ATG7 expression and autophagy was mediated by enhanced expression of BTG1 (B cell translocation gene 1, anti-proliferative) that stimulated activity of CREB1 (cAMP response element binding protein 1). The importance of BTG1 in this regulation was further demonstrated by the observed BAT whitening in adipocyte-specific BTG1-overexpressing mice and the attenuated Dex-induced BAT whitening and fat mass gain in mice with BTG1 knockdown in BAT. Taken together, we showed that Dex induces a significant whitening of BAT via BTG1- and ATG7-dependent autophagy, which might contribute to Dex-increased adiposity. These results provide new insights into the mechanisms underlying GC-increased adiposity and possible strategy for preventing GC-induced side effects via the combined use of an autophagy inhibitor. Abbreviations ACADL: acyl-Coenzyme A dehydrogenase, long-chain; ACADM: acyl-Coenzyme A dehydrogenase, medium-chain; ACADS: acyl-Coenzyme A dehydrogenase, short-chain; ADIPOQ: adiponectin; AGT: angiotensinogen; Atg: autophagy-related; BAT: brown adipose tissue; BTG1: B cell translocation gene 1, anti-proliferative; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; CIDEA: cell death-inducing DNA fragmentation factor, alpha subunit-like effector A; CPT1B: carnitine palmitoyltransferase 1b, muscle; CPT2: carnitine palmitoyltransferase 2; CQ: chloroquine; Dex: dexamethasone; eWAT: epididymal white adipose tissue; FABP4: fatty acid binding protein 4, adipocyte; FFAs: free fatty acids; GCs: glucocorticoids; NRIP1: nuclear receptor interacting protein 1; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PPARA: peroxisome proliferator activated receptor alpha; PPARG: peroxisome proliferator activated receptor gamma; PPARGC1A: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; PRDM16: PR domain containing 16; PSAT1: phosphoserine aminotransferase 1; RB1: RB transcriptional corepressor 1; RBL1/p107: RB transcriptional corepressor like 1; SQSTM1: sequestosome 1; sWAT: subcutaneous white adipose tissue; TG: triglycerides; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); WT: wild-type