Hazegh Kelsey E, Nemkov Travis, D'Alessandro Angelo, Diller John D, Monks Jenifer, McManaman James L, Jones Kenneth L, Hansen Kirk C, Reis Tânia
Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO United States of America.
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO United States of America.
PLoS Genet. 2017 Jun 22;13(6):e1006859. doi: 10.1371/journal.pgen.1006859. eCollection 2017 Jun.
Preventing obesity requires a precise balance between deposition into and mobilization from fat stores, but regulatory mechanisms are incompletely understood. Drosophila Split ends (Spen) is the founding member of a conserved family of RNA-binding proteins involved in transcriptional regulation and frequently mutated in human cancers. We find that manipulating Spen expression alters larval fat levels in a cell-autonomous manner. Spen-depleted larvae had defects in energy liberation from stores, including starvation sensitivity and major changes in the levels of metabolic enzymes and metabolites, particularly those involved in β-oxidation. Spenito, a small Spen family member, counteracted Spen function in fat regulation. Finally, mouse Spen and Spenito transcript levels scaled directly with body fat in vivo, suggesting a conserved role in fat liberation and catabolism. This study demonstrates that Spen is a key regulator of energy balance and provides a molecular context to understand the metabolic defects that arise from Spen dysfunction.
预防肥胖需要在脂肪储存的沉积与动员之间达到精确的平衡，但相关调节机制尚未完全明确。果蝇“裂端”（Spen）是一个保守的RNA结合蛋白家族的创始成员，该家族参与转录调控，且在人类癌症中经常发生突变。我们发现，操纵Spen的表达会以细胞自主的方式改变幼虫的脂肪水平。Spen缺失的幼虫在从储存中释放能量方面存在缺陷，包括饥饿敏感性以及代谢酶和代谢物水平的重大变化，尤其是那些参与β-氧化的物质。Spenito是Spen家族的一个小成员，它在脂肪调节中抵消了Spen的功能。最后，小鼠体内Spen和Spenito的转录水平与体脂直接相关，表明它们在脂肪释放和分解代谢中具有保守作用。这项研究表明，Spen是能量平衡的关键调节因子，并为理解由Spen功能障碍引起的代谢缺陷提供了分子背景。
