CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Autophagy. 2020 Mar;16(3):451-465. doi: 10.1080/15548627.2019.1628537. Epub 2019 Jun 18.
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. 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.
糖皮质激素（GC）引起肥胖的机制尚不清楚。棕色脂肪组织（BAT）在某些情况下获得了白色脂肪组织（WAT）的特征，被定义为 BAT 白化。我们目前的研究目的是研究 GC 诱导的 BAT 白化的可能性和机制。在这里，我们表明，一周的地塞米松（Dex）处理在体外和体内诱导了 BAT 白化，其特征是脂滴积累。此外，Dex 诱导了 BAT 中的自噬和 ATG7（自噬相关 7）表达，自噬抑制剂氯喹或腺病毒介导的 ATG7 敲低可预防 Dex 诱导的 BAT 白化和脂肪量增加。此外，Dex 通过增强 BTG1（增殖抑制的 B 细胞易位基因 1）的表达来增加 ATG7 表达和自噬，从而刺激 CREB1（cAMP 反应元件结合蛋白 1）的活性。BTG1 在这种调节中的重要性进一步通过在脂肪细胞特异性过表达 BTG1 的小鼠中观察到的 BAT 白化以及在 BAT 中敲低 BTG1 的小鼠中观察到的 Dex 诱导的 BAT 白化和脂肪量增加得到证实。总之，我们表明 Dex 通过 BTG1 和 ATG7 依赖性自噬显著诱导 BAT 白化，这可能导致 Dex 引起的肥胖。这些结果为 GC 引起肥胖的机制提供了新的见解，并为通过联合使用自噬抑制剂预防 GC 诱导的副作用提供了可能的策略。ACADL：长链酰基辅酶 A 脱氢酶；ACADM：中链酰基辅酶 A 脱氢酶；ACADS：短链酰基辅酶 A 脱氢酶；脂联素；血管紧张素原；Atg：自噬相关；BAT：棕色脂肪组织；BTG1：增殖抑制的 B 细胞易位基因 1；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 亚单位样效应物 A；肉碱棕榈酰转移酶 1b，肌肉；肉碱棕榈酰转移酶 2；氯喹；地塞米松；附睾白色脂肪组织；脂肪细胞脂肪酸结合蛋白 4；游离脂肪酸；GCs：糖皮质激素；NRIP1：核受体相互作用蛋白 1；耗氧量；磷酸盐缓冲盐水；过氧化物酶体增殖物激活受体 alpha；过氧化物酶体增殖物激活受体 gamma；过氧化物酶体增殖物激活受体，γ，共激活因子 1α；PRDM16：PR 结构域包含 16；磷酸丝氨酸转氨酶 1；RB1：RB 转录核心阻遏物 1；RBL1/p107：RB 转录核心阻遏物样 1；自噬相关蛋白 1；皮下白色脂肪组织；三酰基甘油；解偶联蛋白 1（线粒体，质子载体）；野生型。
