PDF(Pubmed)
Abstract：
Organisms experience constant nutritional flux. Mechanisms at the interface of opposing nutritional states-scarcity and surplus-enable organismal energy homeostasis. Contingent on nutritional stores, adipocytes secrete adipokines, such as the fat hormone leptin, to signal nutrient status to the central brain. Increased leptin secretion underlies metabolic dysregulation during common obesity, but the molecular mechanisms regulating leptin secretion from human adipocytes are poorly understood. Here, we report that Atg8/LC3 family proteins, best known for their role in autophagy during nutrient scarcity, play an evolutionarily conserved role during nutrient surplus by promoting adipokine secretion. We show that in a well-fed state, Atg8/LC3 promotes the secretion of the Drosophila functional leptin ortholog unpaired 2 (Upd2) and leptin from human adipocytes. Proteomic analyses reveal that LC3 directs leptin to a secretory pathway in human cells. We identified LC3-dependent extracellular vesicle (EV) loading and secretion (LDELS) as a required step for leptin release, highlighting a unique secretory route adopted by leptin in human adipocytes. In Drosophila, mutations to Upd2\'s Atg8 interaction motif (AIM) result in constitutive adipokine retention. Atg8-mediated Upd2 retention alters lipid storage and hunger response and rewires the bulk organismal transcriptome in a manner conducive to starvation survival. Thus, Atg8/LC3\'s bidirectional role in nutrient sensing-conveying nutrient surplus and responding to nutrient deprivation-enables organisms to manage nutrient flux effectively. We posit that decoding how bidirectional molecular switches-such as Atg8/LC3-operate at the nexus of nutritional scarcity and surplus will inform therapeutic strategies to tackle chronic metabolic disorders.
摘要：
生物体经历不断的营养流动。相反的营养状态-稀缺和过剩-使机体能量稳态的界面机制。有营养商店，脂肪细胞分泌脂肪因子，比如脂肪激素瘦素，向中枢大脑发出营养状况的信号。瘦素分泌增加是常见肥胖期间代谢失调的基础，但是调节人脂肪细胞分泌瘦素的分子机制却知之甚少。这里,我们报道了Atg8/LC3家族蛋白，最著名的是它们在营养缺乏期间的自噬中的作用，通过促进脂肪因子分泌，在营养过剩期间发挥进化保守作用。我们表明，在一个吃饱的国家，Atg8/LC3促进来自人脂肪细胞的果蝇功能性瘦素直系同源物2(Upd2)和瘦素的分泌。蛋白质组学分析显示，LC3将瘦素引导到人细胞的分泌途径。我们确定LC3依赖的细胞外囊泡（EV）负荷和分泌（LDELS）是瘦素释放所需的步骤，强调瘦素在人脂肪细胞中采用的独特分泌途径。在果蝇中,Upd2的Atg8相互作用基序（AIM）的突变导致组成型脂肪因子保留。Atg8介导的Upd2保留改变了脂质储存和饥饿反应，并以有利于饥饿生存的方式重新连接了大量有机转录组。因此，Atg8/LC3在养分感知中的双向作用-输送养分过剩和响应养分剥夺-使生物体能够有效地管理养分通量。我们认为，解码双向分子开关（如Atg8/LC3）如何在营养匮乏和过剩的关系中起作用，将为解决慢性代谢紊乱的治疗策略提供信息。
