Regulation in obese gene expression and adipocyte differentiation by tumor necrosis factor-α.

肿瘤坏死因子-α 调节肥胖基因表达和脂肪细胞分化。

• 批准号: 10672093
• 负责人: UCHIDA Yoko
• 金额: $ 2.43万
• 依托单位: Tokyo Women's Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10672093/
• 关键词: brown adipocytes; tumor necrosis factor-α; obese gene; leptin; protein kinase C; gene expression; 腫瘍壊死因子

Previously we showed that tumor necrosis factor-α(TNF-α) inhibits lipoprotein lipase (LPL) activity and its gene expression, an early marker of adipocyte differentiation, in cultured brown adipocytes. To know whether TFN-αalso affects late events in brown adipocyte maturation, we examined the effect of TFN-α on obese gene expression and leptin secretion in mouse brown adipocytes differentiated in culture. TNF-α caused a concentration-dependent decrease in leptin accumulation in culture medium and leptin mRNA abundance in brown adipocytes which constitutively express the ob gene. Time-course study showed that TNF-α significantly suppressed leptin secretion during incubation for 16, 24 and 48 h. Since some effects of TNF-α are mediated by activation of protein kinase C (PKC), the role of PKC in TNF-α-induced down regulation of ob gene expression and leptin secretion was studied. The suppressive effect of TNF-α on both ob gene expression and leptin secretion was blocked by PKC inhibitors such as bisindolylmaleimide I (BIM) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7). Incubation of brown adipocytes with TNF-α(20 ng/ml, 15 min) caused a rapid shift of PKC activity from the cytosol to the membrane fraction, suggesting an activation of PKC by TNF-α in brown adipocytes. This effect of TNF-α was blocked by a selective PKC inhibitor, BIM. These results suggest that TNF-α promotes dedifferentiation of the brown adipocytes as evidenced by a down regulation in ob gene expression and leptin secretion via PKC-dependent mechanisms.

以前我们发现，肿瘤坏死因子-α（TNF-α）抑制脂蛋白脂酶（LPL）的活性及其基因表达，脂肪细胞分化的早期标志物，在培养的棕色脂肪细胞。为了了解TFN-α是否也影响棕色脂肪细胞成熟的晚期事件，我们检测了TFN-α对培养中分化的小鼠棕色脂肪细胞中肥胖基因表达和瘦素分泌的影响。TNF-α可引起培养基中瘦素积累的浓度依赖性降低和组成性表达ob基因的棕色脂肪细胞中瘦素mRNA丰度的降低。TNF-α在孵育16、24和48 h时显著抑制瘦素的分泌。由于TNF-α的某些作用是通过激活蛋白激酶C（PKC）介导的，因此研究了PKC在TNF-α诱导的ob基因表达和瘦素分泌下调中的作用。TNF-α对ob基因表达和瘦素分泌的抑制作用可被PKC抑制剂双吲哚马来酰亚胺I（BIM）和1-（5-异喹啉磺酰基）-2-甲基哌嗪二盐酸盐（H-7）阻断。用TNF-α（20 ng/ml，15 min）孵育棕色脂肪细胞，可使PKC活性迅速从胞浆转移到膜组分，提示TNF-α可激活棕色脂肪细胞中的PKC。TNF-α的这种作用可被选择性PKC抑制剂BIM阻断。这些结果表明TNF-α通过PKC依赖性机制下调ob基因表达和瘦素分泌，从而促进棕色脂肪细胞的去分化。

项目成果

Y,Uchida et al.: "Protein kinase C mediates tumor necrosis factor-α-induced inhibition of obese gene expression and leption secretion in brown adipocytes"Naunyn-schmiedeberg's Archives of Pharmacology. 360. 691-698 (1999)

Y，Uchida 等人：“蛋白激酶 C 介导肿瘤坏死因子-α 诱导的棕色脂肪细胞中肥胖基因表达和瘦素分泌的抑制”Naunyn-schmiedeberg 药理学档案 360. 691-698 (1999)。

Yoko UCHIDA, Fujiko TSUKAHARA, Ken-ichi OHBA, Akira OGAWA, Toshimasa YOSHIOKA & Takamura MURAKI: "An activation of protein kinase C suppresses obese gene expression and leptin secretion in cultured brown adipocytes"Jpn. J. Pharmacol.. 79 Suppl I. 154 (199

内田洋子、冢原不二子、大场健一、小川晃、吉冈丰正

内田庸子 他: "培養褐色脂肪細胞における腫瘍壊死因子によるobese gene遺伝子発現の抑制"Japanese Journal of Pharmacology. 76・Suppl I. 267P (1998)

Yoko Uchida 等：“培养的棕色脂肪细胞中肿瘤坏死因子对肥胖基因表达的抑制”日本药理学杂志 76·Suppl I.267P (1998)

Yoko UCHIDA, Fujiko TSUKAHRA, Ken-ichi OHBA, Akira OGAWA, Toshismasa YOSHIOKA & Takamura MURAKI: "Tumor necrosis factor-α suppresses obese gene expression in cultured brown adipocytes"Jpn. J. Pharmacol.. 76 Suppl I. 267 (1998)

Yoko UCHIDA、Fujiko TSUKAHRA、Ken-ichi OHBA、Akira OGAWA、Toshismasa YOSHIOKA 和 Takamura MURAKI：“肿瘤坏死因子-α 抑制培养棕色脂肪细胞中的肥胖基因表达”Jpn. J. Pharmacol.. 76 Suppl I. 267 (1998)

Y,Uchida et al.: "Attenuated responses to tumor necrosis factor-α(TNF-α)in brown adipocytes derived from inducible nitric oxide synthase-deficient mice"Acta Physiologica Scandinavica. 167suppl645. 80 (1999)

Y，Uchida 等人：“源自诱导型一氧化氮合酶缺陷型小鼠的棕色脂肪细胞对肿瘤坏死因子-α (TNF-α) 的减弱反应”Acta Physiologica Scandinavica 167suppl645。