BACKGROUND Increasing adaptive thermogenesis in adipose tissue may be a potential therapeutic target for overcoming obesity and obesity-related disorders. Preadipocyte factor 1 (Pref-1), a preadipocyte secreted protein, plays an inhibitory role in adipogenic differentiation. However, the role of Pref-1 in adipose tissue browning remains unknown. We investigated whether Pref-1 regulates thermogenic program and beige fat biogenesis. METHODS Pref-1 expression levels were examined in inguinal white adipose tissue (iWAT) and differentiated 3T3-L1 adipocytes in thermogenic conditions induced by cold exposure or a beta-adrenergic stimulus (CL316,243). Overexpression and knockdown studies were performed both in vivo and in vitro to clarify the role of Pref-1 in iWAT browning. RESULTS Cold exposure or CL316,243 induced a thermogenic program in adipose tissue of C57BL/6N mice and in 3T3-L1 adipocytes. Notably, Pref-1 levels were down-regulated in iWAT and adipocytes under these conditions. Overexpressing Pref-1 showed reduced thermogenic gene expressions in response to CL316,243 treatment, whereas depletion of Pref-1 augmented thermogenic program in 3T3-L1 adipocytes. Correspondingly, treating C57BL/6N mice with Pref-1 resulted in reduced expression of thermogenic and beige fat markers, a reduced rate of oxygen consumption, blunting of UCP1 expression and beige fat formation in iWAT in response to cold exposure or CL316,243 injection compared to the untreated mice. The opposite phenotype was observed in mice with inducible fat-specific knock-out of Pref-1. Mechanistically, these effects were regulated by modulation of TNF-α-converting enzyme activity and Pref-1 cleavage. CONCLUSION Our findings establish a novel role of Pref-1 that regulates adaptive thermogenesis. This offers a unique target for improving energy homeostasis and treating obesity.

中文翻译：

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前脂肪细胞因子1通过TNF-α转换酶介导的裂解调节脂肪组织的褐变。

背景技术在脂肪组织中增加适应性生热可能是克服肥胖症和与肥胖症有关的疾病的潜在治疗靶标。前脂肪细胞分泌蛋白Preadipocyte factor 1（Pref-1）在成脂分化中起抑制作用。但是，Pref-1在脂肪组织褐变中的作用仍然未知。我们调查了Pref-1是否调节生热程序和米色脂肪的生物发生。方法在冷暴露或β-肾上腺素刺激（CL316，243）诱导的产热条件下，检查腹股沟白色脂肪组织（iWAT）和分化的3T3-L1脂肪细胞中Pref-1的表达水平。在体内和体外均进行了过表达和击倒研究，以阐明Pref-1在iWAT褐变中的作用。结果冷暴露或CL316，243在C57BL / 6N小鼠的脂肪组织和3T3-L1脂肪细胞中诱导了产热程序。值得注意的是，在这些条件下，iWAT和脂肪细胞中的Pref-1水平下调。过表达的Pref-1显示响应CL316,243处理而降低了生热基因表达，而枯竭的Pref-1增强了3T3-L1脂肪细胞中的生热程序。相应地，与Pref-1相比，用Pref-1处理C57BL / 6N小鼠导致iWAT中冷暴露或CL316,243注射引起的产热和米色脂肪标记物表达降低，耗氧率降低，UCP1表达钝化和米色脂肪形成。给未治疗的小鼠。在具有可诱导的脂肪特异性敲除Pref-1的小鼠中观察到相反的表型。机械上，这些作用是通过调节TNF-α转换酶活性和Pref-1裂解来调节的。结论我们的发现建立了Pref-1的新作用，该作用调节适应性生热作用。这为改善能量稳态和治疗肥胖症提供了独特的目标。