Heme oxygenase-mediated increases in adiponectin decrease fat content and inflammatory cytokines tumor necrosis factor-α and interleukin-6 in Zucker rats and reduce adipogenesis in human mesenchymal stem cells
Heme oxygenase-mediated increases in adiponectin decrease fat content and inflammatory cytokines tumor necrosis factor-α and interleukin-6 in Zucker rats and reduce adipogenesis in human mesenchymal stem cells
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DOI：
10.1124/jpet.107.135285
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发表时间：
2008-06-01
影响因子：
3.5
通讯作者：
Abraham, Nader G.
中科院分区：
文献类型：
--
作者：
Kim, Dong Hyun;Burgess, Angela P.;Abraham, Nader G.
脂联素是一种丰富的脂肪细胞源性血浆蛋白，可调节2型糖尿病患者的血管功能，已被证明对糖尿病患者的胰腺和血管系统具有细胞保护作用。因此，我们研究了血红素氧合酶（HO）-1的上调是否改善炎症细胞因子的水平，并影响Zucker脂肪（ZF）大鼠血清脂联素。与Zucker lean（ZL）大鼠相比，ZF大鼠显示HO活性和HO-1和HO-2蛋白水平降低，肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6升高。用2 mg/kg钴原卟啉IX（CoPP）处理ZF动物可增加HO-1和HO活性的蛋白水平，但HO-2不受影响。与未治疗的ZF大鼠相比，HO-1的增加与超氧化物水平的降低（p < 0.05）和血浆脂联素的增加（p < 0.005）相关。CoPP处理降低了内脏和s.c.脂肪含量，并降低体重增长（P < 0.01）。此外，炎性细胞因子TNF-α和IL-6降低（分别为p < 0.04和p < 0.008）。用CoPP培养的人骨髓源性脂肪细胞的处理导致HO-1的增加和超氧化物水平的降低。HO-1的上调导致人骨髓源性脂肪细胞培养基中脂肪重塑、脂肪细胞变小并增加脂联素分泌。总之，本研究表明HO-1诱导的抗肥胖作用导致体内和体外脂联素分泌增加，TNF-α和IL-6减少，体重增加减少。这些发现强调了HO-1和脂联素在代谢综合征表型调节中的关键作用和共生关系。
Adiponectin, an abundant adipocyte-derived plasma protein that modulates vascular function in type 2 diabetes, has been shown to provide cytoprotection to both pancreatic and vascular systems in diabetes. Therefore, we examined whether up-regulation of heme oxygenase (HO)-1 ameliorates the levels of inflammatory cytokines and influences serum adiponectin in Zucker fat (ZF) rats. ZF rats displayed a decrease in both HO activity and HO-1 and HO-2 protein levels and an increase in tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 compared with Zucker lean (ZL) rats. Treatment of ZF animals with 2 mg/kg cobalt protoporphyrin IX (CoPP) increased protein levels of HO-1 and HO activity, but HO-2 was unaffected. The increase in HO-1 was associated with a decrease in superoxide levels (p < 0.05) and an increase in plasma adiponectin (p < 0.005), compared with untreated ZF rats. CoPP treatment decreased visceral and s.c. fat content, and it reduced weight gain (p < 0.01). In addition, the inflammatory cytokines TNF-alpha and IL-6 were decreased (p < 0.04 and p < 0.008, respectively). Treatment of human bone marrow-derived adipocytes cultured with CoPP resulted in an increase in HO-1 and a decrease in superoxide levels. Up-regulation of HO-1 caused adipose remodeling, smaller adipocytes, and increased adiponectin secretion in the culture medium of human bone marrow-derived adipocytes. In summary, this study demonstrates that the antiobesity effect of HO-1 induction results in an increase in adiponectin secretion, in vivo and in vitro, a decrease in TNF-alpha and IL-6, and a reduction in weight gain. These findings highlight the pivotal role and symbiotic relationship of HO-1 and adiponectin in the modulation of the metabolic syndrome phenotype.