Department of Oral Biochemistry, Field of Developmental Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, U.S.A.
Biochem J. 2019 Nov 29;476(22):3533-3548. doi: 10.1042/BCJ20190709.
Hypoxia in adipose tissue is regarded as a trigger that induces dysregulation of the secretory profile in adipocytes. Similarly, local dysregulation of adipocytokine secretion is an initial event in the deleterious effects of obesity on metabolism. We previously reported that CXCL13 is highly produced during adipogenesis, however little is known about the roles of CXCL13 in adipocytes. Here, we found that hypoxia, as modeled by 1% O2 or exposure to the hypoxia-mimetic reagent desferrioxamine (DFO) has strong inductive effects on the expression of CXCL13 and CXCR5, a CXCL13 receptor, in both undifferentiated and differentiated adipocytes and in organ-cultured white adipose tissue (WAT). CXCL13 was also highly expressed in WAT from high fat diet-fed mice. Hypoxic profile, typified by increased expression of interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) and decreased expression of adiponectin, was significantly induced by CXCL13 treatment during adipogenic differentiation. Conversely, the treatment of adipocytes with a neutralizing-antibody against CXCL13 as well as CXCR5 knockdown by specific siRNA effectively inhibited DFO-induced inflammation. The phosphorylation of Akt2, a protective factor of adipose inflammation, was significantly inhibited by CXCL13 treatment during adipogenic differentiation. Mechanistically, CXCL13 induces the expression of PHLPP1, an Akt2 phosphatase, through focal adhesion kinase (FAK) signaling; and correspondingly we show that CXCL13 and DFO-induced IL-6 and PAI-1 expression was blocked by Phlpp1 knockdown. Furthermore, we revealed the functional binding sites of PPARγ2 and HIF1-α within the Cxcl13 promoter. Taken together, these results indicate that CXCL13 is an adipocytokine that facilitates hypoxia-induced inflammation in adipocytes through FAK-mediated induction of PHLPP1 in autocrine and/or paracrine manner.
脂肪组织缺氧被认为是诱导脂肪细胞分泌失调的触发因素。同样，脂肪细胞因子分泌的局部失调是肥胖对代谢产生有害影响的初始事件。我们之前报道过，在脂肪生成过程中 CXCL13 大量产生，但对于 CXCL13 在脂肪细胞中的作用知之甚少。在这里，我们发现，1%O2 或缺氧模拟试剂去铁胺（DFO）模拟的缺氧对未分化和分化的脂肪细胞以及器官培养的白色脂肪组织（WAT）中 CXCL13 和 CXCL13 受体 CXCR5 的表达有很强的诱导作用。高脂肪饮食喂养的小鼠的 WAT 中也高度表达 CXCL13。在脂肪生成分化过程中，CXCL13 处理显著诱导了缺氧特征，表现为白细胞介素 6（IL-6）和纤溶酶原激活物抑制剂-1（PAI-1）表达增加，脂联素表达减少。相反，用针对 CXCL13 的中和抗体或特异性 siRNA 敲低 CXCR5 处理脂肪细胞可有效抑制 DFO 诱导的炎症。在脂肪生成分化过程中，CXCL13 处理显著抑制了 Akt2 的磷酸化，Akt2 是脂肪炎症的保护因子。在机制上，CXCL13 通过粘着斑激酶（FAK）信号诱导 Akt2 磷酸酶 PHLPP1 的表达；相应地，我们表明 CXCL13 和 DFO 诱导的 IL-6 和 PAI-1 表达被 Phlpp1 敲低所阻断。此外，我们揭示了 PPARγ2 和 HIF1-α 在 Cxcl13 启动子内的功能结合位点。总之，这些结果表明，CXCL13 是一种脂肪细胞因子，通过 FAK 介导的自分泌和/或旁分泌方式诱导 PHLPP1 的表达，从而促进脂肪细胞缺氧诱导的炎症。
