Effects of wnt signaling on brown adipocyte differentiation and metabolism mediated by PGC-1α
Effects of wnt signaling on brown adipocyte differentiation and metabolism mediated by PGC-1α
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DOI：
10.1128/mcb.25.4.1272-1282.2005
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发表时间：
2005-02-01
影响因子：
5.3
通讯作者：
MacDougald, OA
中科院分区：
文献类型：
--
作者：
Kang, S;Bajnok, L;MacDougald, OA
经典Wnt信号传导的激活通过阻碍PPARgamma和C/EBPalpha的诱导来抑制培养细胞的棕色脂肪形成。尽管这些脂肪形成转录因子的强制表达恢复了Wnt表达细胞中的脂质积累和FABP 4的表达，但解偶联蛋白1（UCP 1）的激活需要PGC-1 α的额外表达。当从脂肪酸结合蛋白4启动子表达时，Wnt 10 b阻断棕色脂肪组织发育和UCP 1表达，即使当小鼠被给予β 3-激动剂时也是如此。在分化的棕色脂肪细胞中，Wnt信号的激活通过抑制PGC-1 α抑制UCP 1的表达。与这些体外观察结果一致，在肩胛间组织中表达Wnt 10 b的UCP 1-Wnt 10 b转基因小鼠缺乏功能性棕色脂肪组织。虽然UCP 1-Wnt 10 b小鼠的肩胛间组织缺乏PGC-1 α和UCP 1的表达，但单室脂滴的存在和白色脂肪细胞基因的表达表明棕色脂肪组织转化为白色。在来自冷激或遗传性肥胖小鼠的肩胛间组织中，Wnt 10 b与UCP 1和PGC-1 α的相互表达为Wnt信号传导调节棕色脂肪细胞代谢提供了进一步的证据。总之，这些数据表明，在分化早期激活经典Wnt信号传导阻断棕色脂肪形成，而在成熟棕色脂肪细胞中激活Wnt信号传导刺激其转化为白色脂肪细胞。
Activation of canonical Wnt signaling inhibits brown adipogenesis of cultured cells by impeding induction of PPARgamma and C/EBPalpha. Although enforced expression of these adipogenic transcription factors restores lipid accumulation and expression of FABP4 in Wnt-expressing cells, additional expression of PGC-1alpha is required for activation of uncoupling protein 1 (UCP1). Wnt10b blocks brown adipose tissue development and expression of UCP1 when expressed from the fatty acid binding protein 4 promoter, even when mice are administered a beta3-agonist. In differentiated brown adipocytes, activation of Wnt signaling suppresses expression of UCP1 through repression of PGC-1alpha. Consistent with these in vitro observations, UCP1-Wnt10b transgenic mice, which express Wnt10b in interscapular tissue, lack functional brown adipose tissue. While interscapular tissue of UCP1-Wnt10b mice lacks expression of PGC-1alpha and UCP1, the presence of unilocular lipid droplets and expression of white adipocyte genes suggest conversion of brown adipose tissue to white. Reciprocal expression of Wnt10b with UCP1 and PGC-1alpha in interscapular tissue from cold-challenged or genetically obese mice provides further evidence for regulation of brown adipocyte metabolism by Wnt signaling. Taken together, these data suggest that activation of canonical Wnt signaling early in differentiation blocks brown adipogenesis, whereas activating Wnt signaling in mature brown adipocytes stimulates their conversion to white adipocytes.