Extracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.

中文翻译：

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酰基辅酶A结合蛋白用于实验性治疗厌食症


细胞外酰基辅酶 A 结合蛋白 [由地西泮结合抑制剂 (DBI) 编码的 ACBP] 是一种系统发育古老的食欲刺激剂，以非传统的自噬依赖性方式分泌。在这里，我们发现低 ACBP/DBI 血浆浓度与神经性厌食症患者的不良预后相关，神经性厌食症是一种常见且往往难以治愈的饮食失调症。在小鼠中，慢性束缚应激 (CRS) 引起的厌食症伴随着循环 ACBP/DBI 浓度的降低。我们设计了一个化学遗传系统，通过生物素可激活、不依赖自噬的途径分泌 ACBP/DBI。在肝细胞中表达该系统的转基因小鼠中，生物素诱导的血浆 ACBP/DBI 浓度升高可防止 CRS 或化疗药物（包括顺铂、阿霉素和紫杉醇）诱导的厌食症。 ACBP/DBI 逆转了 CRS 或顺铂诱导的血浆 lipocalin-2 浓度增加和下丘脑抑制食欲的黑皮质素 4 受体的激活，lipocalin-2 是该受体的激动剂。每日静脉注射重组 ACBP/DBI 蛋白或皮下植入释放重组 ACBP/DBI 的渗透泵模拟了化学遗传系统的食欲促进作用。总之，补充细胞外和外周 ACBP/DBI 可能构成治疗厌食症的可行策略。