Adipocyte integrin-linked kinase plays a key role in the development of diet-induced adipose insulin resistance in male mice.
Adipocyte integrin-linked kinase plays a key role in the development of diet-induced adipose insulin resistance in male mice.
复制标题
脂肪细胞整合素连接激酶在雄性小鼠饮食诱导的脂肪胰岛素抵抗的发展中起着关键作用。
DOI：
10.1016/j.molmet.2021.101197
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发表时间：
2021-07
影响因子：
8.1
通讯作者：
Kang L
中科院分区：
文献类型：
--
作者：
Bugler-Lamb AR;Hasib A;Weng X;Hennayake CK;Lin C;McCrimmon RJ;Stimson RH;Ashford MLJ;Wasserman DH;Kang L
肥胖期间脂肪组织（AT）中细胞外基质（ECM）的增加的沉积有助于胰岛素抵抗。整合素受体传递细胞外环境的变化，引起相应的细胞内适应。整合素连接激酶（ILK）是一种衔接蛋白，是整合素细胞内信号传导的中心枢纽。本研究确定了ILK在脂肪功能和胰岛素抵抗中的作用。在人脂肪组织和脂肪细胞特异性ILK缺陷小鼠（ILKlox/loxAdCre）中研究了ILK在肥胖和胰岛素抵抗中的致病作用。将ILKlox/loxAdCre小鼠与野生型同窝小鼠（ILKlox/lox）一起喂食普通饲料或60%高脂肪（HF）饲料16周。体内胰岛素敏感性通过高胰岛素-正常血糖钳夹测定。在小鼠中通过HF饮食喂养增加AT ILK表达，并且在病态肥胖的人的内脏脂肪中增加。相对于HF喂养的ILKlox/lox小鼠，HF喂养的ILKlox/loxAdCre小鼠显示出减少的脂肪量和改善的葡萄糖耐量。在高胰岛素-正常血糖钳夹期间，HF喂养的ILKlox/loxAdCre小鼠在AT中表现出部分改善的胰岛素抵抗。脂肪分解被抑制到更大程度的胰岛素和葡萄糖摄取棕色AT（BAT）增加。脂解抑制的增加可能归因于白色AT中血管化的增加，而BAT中葡萄糖摄取的增加与Akt磷酸化和P38/JNK去磷酸化的增加相关。值得注意的是，瘦小鼠的AT胰岛素敏感性不受ILK缺失的影响。此外，HF喂养的ILKlox/loxAdCre小鼠的脂肪量减少可能归因于通过下调CD 36基因表达减少脂肪细胞中的游离脂肪酸摄取。与小鼠中的结果一致，3 T3-L1细胞中ILK的敲低和敲除降低了脂肪形成期间的脂质积累和CD 36基因表达。这些数据表明，脂肪细胞ILK是重要的调节HF饮食介导的胰岛素抵抗AT的方式与AT功能一致。ILK蛋白在肥胖的人和小鼠的内脏脂肪组织中增加。缺乏脂肪细胞ILK的小鼠在肥胖症中脂肪更少，葡萄糖耐量提高。脂肪细胞ILK缺失改善胰岛素在肥胖小鼠中的抗脂肪分解作用。脂肪细胞ILK缺失刺激肥胖小鼠棕色脂肪组织葡萄糖摄取。
Increased deposition of the extracellular matrix (ECM) in adipose tissue (AT) during obesity contributes to insulin resistance. The integrin receptors transmit changes in the extracellular environment causing corresponding intracellular adaptations. Integrin-linked kinase (ILK), an adaptor protein, is a central hub for intracellular signaling of integrins. This study determined the role of ILK in adipose function and insulin resistance. The pathogenic role of ILK in obesity and insulin resistance was studied in human adipose tissue and adipocyte-specific ILK-deficient mice (ILKlox/loxAdCre). ILKlox/loxAdCre mice together with wild-type littermates (ILKlox/lox) were fed a chow diet or 60% high-fat (HF) diet for 16 weeks. In vivo insulin sensitivity was determined by hyperinsulinemic-euglycemic clamps. AT ILK expression was increased by HF diet feeding in mice and increased in visceral fat of morbidly obese humans. The HF-fed ILKlox/loxAdCre mice displayed reduced fat mass and improved glucose tolerance relative to the HF-fed ILKlox/lox mice. During a hyperinsulinemic-euglycemic clamp, the HF-fed ILKlox/loxAdCre mice exhibited partially improved insulin resistance in AT. Lipolysis was suppressed to a greater extent by insulin and glucose uptake in brown AT (BAT) increased. Increased inhibition of lipolysis may have been attributed to increased vascularization in white AT, while increased glucose uptake in BAT was associated with increased Akt phosphorylation and P38/JNK dephosphorylation. Notably, AT insulin sensitivity in lean mice was not affected by ILK deletion. Moreover, reduced fat mass in the HF-fed ILKlox/loxAdCre mice may have been attributed to decreased free fatty acid uptake into adipocytes via the downregulation of CD36 gene expression. Consistent with the results in the mice, knockdown and knockout of ILK in 3T3-L1 cells decreased lipid accumulation and CD36 gene expression during adipogenesis. These data show that adipocyte ILK is important for regulating HF diet-mediated insulin resistance in AT in a manner consistent with AT function. ILK protein increased in visceral adipose tissue of obese humans and mice. Mice lacking adipocyte ILK had less fat and improved glucose tolerance in obesity. Adipocyte ILK deletion improved anti-lipolytic action of insulin in obese mice. Adipocyte ILK deletion stimulated brown adipose tissue glucose uptake in obese mice.
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影响因子：
15.9
作者：
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通讯作者：
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影响因子：
5.8
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影响因子：
16.2
作者：
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影响因子：
39.2
作者：
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