ABSTRACT

Although macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood. in this study, we showed that global or brown adipocyte-specific deletion of pink1, a Parkinson disease-related gene involved in selective mitochondrial autophagy (mitophagy), induced BAT dysfunction, and obesity-prone type in mice. Defective mitochondrial function is among the upstream signals that activate the NLRP3 inflammasome. NLRP3 was induced in brown adipocyte precursors (BAPs) from pink1 knockout (KO) mice. Unexpectedly, NLRP3 induction did not induce canonical inflammasome activity. Instead, NLRP3 induction led to the differentiation of pink1 KO BAPs into white-like adipocytes by increasing the expression of white adipocyte-specific genes and repressing the expression of brown adipocyte-specific genes. nlrp3 deletion in pink1 knockout mice reversed BAT dysfunction. Conversely, adipose tissue-specific atg7 KO mice showed significantly lower expression of Nlrp3 in their BAT. Overall, our data suggest that the role of mitophagy is different from general autophagy in regulating adipose tissue and whole-body energy metabolism. Our results uncovered a new mitochondria-NLRP3 pathway that induces BAT dysfunction. The ability of the nlrp3 knockouts to rescue BAT dysfunction suggests the transcriptional function of NLRP3 as an unexpected, but a quite specific therapeutic target for obesity-related metabolic diseases.

Abbreviations: ACTB: actin, beta; BAPs: brown adipocyte precursors; BAT: brown adipose tissue; BMDMs: bone marrow-derived macrophages; CASP1: caspase 1; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; ChIP: chromatin immunoprecipitation; EE: energy expenditure; HFD: high-fat diet; IL1B: interleukin 1 beta; ITT: insulin tolerance test; KO: knockout; LPS: lipopolysaccharide; NLRP3: NLR family, pyrin domain containing 3; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RD: regular diet; ROS: reactive oxygen species; RT: room temperature; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); WT: wild-type.

 抽象的

尽管巨自噬/自噬缺陷会导致退行性疾病，但脂肪细胞中必需自噬基因的缺失反而会降低体重。棕色脂肪组织（BAT）在体重调节和代谢控制中发挥着重要作用。然而，维持 BAT 功能的关键细胞机制仍知之甚少。在这项研究中，我们发现， pink1 （一种参与选择性线粒体自噬（mitophagy）的帕金森病相关基因）的整体或棕色脂肪细胞特异性缺失，可诱导小鼠的 BAT 功能障碍和肥胖倾向类型。线粒体功能缺陷是激活 NLRP3 炎症小体的上游信号之一。 NLRP3 在来自Pink1敲除 (KO) 小鼠的棕色脂肪细胞前体 (BAP) 中被诱导。出乎意料的是，NLRP3 诱导并未诱导典型的炎症小体活性。相反，NLRP3诱导通过增加白色脂肪细胞特异性基因的表达并抑制棕色脂肪细胞特异性基因的表达，导致pink1 KO BAP分化为白色脂肪细胞。 Pink1敲除小鼠中nlrp3缺失逆转了 BAT 功能障碍。相反，脂肪组织特异性atg7 KO 小鼠的 BAT 中Nlrp3表达显着降低。总的来说，我们的数据表明线粒体自噬在调节脂肪组织和全身能量代谢方面的作用不同于一般的自噬。我们的结果发现了一种新的线粒体-NLRP3 途径，可诱导 BAT 功能障碍。 nlrp3敲除能够挽救 BAT 功能障碍，这表明 NLRP3 的转录功能是肥胖相关代谢疾病的一个意想不到但非常具体的治疗靶点。

缩写： ACTB：肌动蛋白，β； BAP：棕色脂肪细胞前体； BAT：棕色脂肪组织； BMDMs：骨髓来源的巨噬细胞； CASP1: 半胱天冬酶 1; CEBPA：CCAAT/增强子结合蛋白（C/EBP），α； ChIP：染色质免疫沉淀； EE：能量消耗； HFD：高脂肪饮食； IL1B：白细胞介素1β； ITT：胰岛素耐量试验； KO：淘汰赛； LPS：脂多糖； NLRP3：NLR家族，含有3个pyrin结构域； PINK1：PTEN 诱导的推定激酶 1； PRKN：parkin RBR E3 泛素蛋白连接酶； RD：规律饮食； ROS：活性氧； RT：室温； UCP1：解偶联蛋白1（线粒体、质子载体）； WT：野生型。