ABSTRACT

Adipose tissue (AT) fibrosis in obesity compromises adipocyte functions and responses to intervention-induced weight loss. It is driven by AT progenitors with dual fibro/adipogenic potential, but pro-fibrogenic pathways activated in obesity remain to be deciphered. To investigate the role of macroautophagy/autophagy in AT fibrogenesis, we used Pdgfra-Cre^Ert2 transgenic mice to create conditional deletion of Atg7 alleles in AT progenitor cells (atg7 cKO) and examined sex-dependent, depot-specific AT remodeling in high-fat diet (HFD)-fed mice. Mice with atg7 cKO had markedly decreased extracellular matrix (ECM) gene expression in visceral, subcutaneous, and epicardial adipose depots compared to Atg7^lox/lox littermates. ECM gene program regulation by autophagy inhibition occurred independently of changes in the mass of fat tissues or adipocyte numbers of specific depots, and cultured preadipocytes treated with pharmacological or siRNA-mediated autophagy disruptors could mimic these effects. We found that autophagy inhibition promotes global cell-autonomous remodeling of the paracrine TGF-BMP family landscape, whereas ECM gene modulation was independent of the autophagic regulation of GTF2IRD1. The progenitor-specific mouse model of ATG7 inhibition confirms the requirement of autophagy for white/beige adipocyte turnover, and combined to in vitro experiments, reveal progenitor autophagy dependence for AT fibrogenic response to HFD, through the paracrine remodeling of TGF-BMP factors balance.

Abbreviations: CQ: chloroquine; ECM: extracellular matrix; EpiAT: epididymal adipose tissue; GTF2IRD1: general transcription factor II I repeat domain-containing 1; HFD: high-fat diet; KO: knockout; OvAT: ovarian adipose tissue; PDGFR: platelet derived growth factor receptor; ScAT: subcutaneous adipose tissue; TGF-BMP: transforming growth factor-bone morphogenic protein

摘要

肥胖中的脂肪组织 (AT) 纤维化会损害脂肪细胞功能和对干预诱导的体重减轻的反应。它由具有双重纤维/脂肪生成潜力的 AT 祖细胞驱动，但在肥胖中激活的促纤维生成途径仍有待破译。为了研究巨自噬/自噬在 AT 纤维化中的作用，我们使用Pdgfra-Cre ^Ert2 转基因小鼠在 AT 祖细胞 ( atg7 cKO) 中创建Atg7等位基因的条件性缺失，并检查了高脂肪中的性别依赖性、库特异性 AT 重塑饮食（HFD）喂养的小鼠。小鼠ATG7 CKO相比已显着减少细胞外基质（ECM）中的内脏，皮下的基因表达，和心外膜脂肪库ATG7^lox/lox 同窝仔。通过自噬抑制对 ECM 基因程序的调节与脂肪组织质量或特定仓库的脂肪细胞数量的变化无关，并且用药理学或 siRNA 介导的自噬破坏剂处理的培养的前脂肪细胞可以模拟这些影响。我们发现自噬抑制促进旁分泌 TGF-BMP 家族景观的整体细胞自主重塑，而 ECM 基因调节独立于 GTF2IRD1 的自噬调节。ATG7 抑制的祖细胞特异性小鼠模型证实了自噬对白色/米色脂肪细胞更新的要求，并结合体外实验，通过 TGF-BMP 因子平衡的旁分泌重塑，揭示祖细胞自噬对 HFD 纤维化反应的依赖性。

缩写： CQ：氯喹；ECM：细胞外基质；EpiAT：附睾脂肪组织；GTF2IRD1：一般转录因子II I重复结构域含1；HFD：高脂肪饮食；KO：淘汰赛；OvAT：卵巢脂肪组织；PDGFR：血小板衍生生长因子受体；ScAT：皮下脂肪组织；TGF-BMP：转化生长因子-骨形态发生蛋白