Center for Clinical and Translational Research, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
Cytokine. 2018 Nov;111:434-444. doi: 10.1016/j.cyto.2018.05.023. Epub 2018 Jun 19.
Thermogenic fat is a promising target for new therapies in diabetes and obesity. Understanding how thermogenic fat develops is important to develop rational strategies to treat obesity. Previously, we have shown that Tyk2 and STAT3, part of the JAK-STAT pathway, are necessary for proper development of classical brown fat. Using primary preadipocytes isolated from newborn mice we demonstrate that STAT3 is required for differentiation and robust expression of Uncoupling Protein 1 (UCP1). We also confirm that STAT3 is necessary during the early induction stage of differentiation and is dispensable during the later terminal differentiation stage. The inability of STAT3 preadipocytes to differentiate can be rescued using Wnt ligand secretion inhibitors when applied during the induction stage. Through chemical inhibition and RNAi, we show that it is the canonical β-catenin pathway that is responsible for the block in differentiation; inhibition or knockdown of β-catenin can fully rescue adipogenesis and UCP1 expression in the STAT3 adipocytes. During the induction stage, Wnts 1, 3a, and 10b have increased expression in the STAT3 adipocytes, potentially explaining the increased levels and activity of β-catenin. Our results for the first time point towards an interaction between the JAK/STAT pathway and the Wnt/β-catenin pathway during the early stages of in-vitro adipogenesis.
生热脂肪是糖尿病和肥胖症新疗法的一个有前途的靶点。了解生热脂肪是如何发育的，对于开发合理的肥胖症治疗策略很重要。以前，我们已经表明，JAK-STAT 通路的一部分 Tyk2 和 STAT3 对于经典棕色脂肪的正常发育是必要的。我们使用从新生小鼠中分离的原代前体脂肪细胞证明，STAT3 是分化和 UCP1（解偶联蛋白 1）的强烈表达所必需的。我们还证实，STAT3 在分化的早期诱导阶段是必需的，而在后期的终末分化阶段是可有可无的。在诱导阶段使用 Wnt 配体分泌抑制剂时，可以挽救 STAT3 前体脂肪细胞分化的无能。通过化学抑制和 RNAi，我们表明，正是经典的β-连环蛋白途径导致了分化的阻滞；β-连环蛋白的抑制或敲低可以完全挽救 STAT3 脂肪细胞中的脂肪生成和 UCP1 表达。在诱导阶段，STAT3 脂肪细胞中 Wnt1、3a 和 10b 的表达增加，这可能解释了 β-连环蛋白水平和活性的增加。我们的结果首次表明，在体外脂肪生成的早期阶段，JAK/STAT 通路和 Wnt/β-连环蛋白通路之间存在相互作用。
