The ubiquitin ligase Siah2 regulates obesity-induced adipose tissue inflammation.
The ubiquitin ligase Siah2 regulates obesity-induced adipose tissue inflammation.
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DOI：
10.1002/oby.21220
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发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Floyd ZE
中科院分区：
文献类型：
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作者：
Kilroy G;Carter LE;Newman S;Burk DH;Manuel J;Möller A;Bowtell DD;Mynatt RL;Ghosh S;Floyd ZE
与脂肪细胞肥大相关的慢性、低度脂肪组织炎症是肥胖与胰岛素抵抗之间关系的重要环节。尽管泛素连接酶调节炎症过程，但这些酶在代谢驱动的脂肪组织炎症中的作用相对尚未被探索。在此，我们研究了泛素连接酶 Siah2 对肥胖相关脂肪组织炎症的影响。野生型和 Siah2KO 小鼠以低脂肪或高脂肪饮食喂养 16 周。间接量热法、身体成分、葡萄糖和胰岛素耐受性以及葡萄糖和胰岛素水平也被测定。还分析了基因和蛋白质表达、免疫组织化学、脂肪细胞大小分布和脂肪分解。肥胖 Siah2KO 小鼠脂肪细胞增大与肥胖引起的胰岛素抵抗无关。 Siah2KO 脂肪组织中促炎基因表达、应激激酶信号传导、纤维化和冠状结构减少，并且 Siah2KO 脂肪细胞对胰岛素依赖性脂肪分解抑制更敏感。 Siah2 的缺失会增加参与脂质代谢的 PPARγ 靶基因的表达，并减少受 PPARγ 调节的促炎脂肪因子的表达。 Siah2 将脂肪细胞肥大与脂肪细胞功能障碍以及促炎免疫细胞募集到脂肪组织联系起来。 PPARγ 活性的选择性调节是 Siah2 介导的机制，有助于肥胖引起的脂肪组织炎症。
Chronic, low-grade adipose tissue inflammation associated with adipocyte hypertrophy is an important link in the relationship between obesity and insulin resistance. Although ubiquitin ligases regulate inflammatory processes, the role of these enzymes in metabolically driven adipose tissue inflammation is relatively unexplored. Herein, we examined the effect of the ubiquitin ligase Siah2 on obesity-related adipose tissue inflammation. Wild-type and Siah2KO mice were fed a low or high fat diet for 16 weeks. Indirect calorimetry, body composition, glucose and insulin tolerance were assayed along with glucose and insulin levels. Gene and protein expression, immunohistochemistry, adipocyte size distribution and lipolysis were also analyzed. Enlarged adipocytes in obese Siah2KO mice are not associated with obesity-induced insulin resistance. Proinflammatory gene expression, stress kinase signaling, fibrosis and crown-like structures are reduced in the Siah2KO adipose tissue and Siah2KO adipocytes are more responsive to insulin-dependent inhibition of lipolysis. Loss of Siah2 increases expression of PPARγ target genes involved in lipid metabolism and decreases expression of proinflammatory adipokines regulated by PPARγ. Siah2 links adipocyte hypertrophy with adipocyte dysfunction and recruitment of proinflammatory immune cells to adipose tissue. Selective regulation of PPARγ activity is a Siah2-mediated mechanism contributing to obesity-induced adipose tissue inflammation.