SERPINA3C ameliorates adipose tissue inflammation through the Cathepsin G/Integrin/AKT pathway.
SERPINA3C ameliorates adipose tissue inflammation through the Cathepsin G/Integrin/AKT pathway.
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SERPINA3C 通过组织蛋白酶 G/整合素/AKT 途径改善脂肪组织炎症
DOI：
10.1016/j.molmet.2022.101500
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发表时间：
2022-07
影响因子：
8.1
通讯作者：
Tang, Qi-Qun
中科院分区：
文献类型：
--
作者：
Li, Bai-Yu;Guo, Ying-Ying;Xiao, Gang;Guo, Liang;Tang, Qi-Qun
由于肥胖和胰岛素抵抗的日益普遍，迫切需要更好地治疗肥胖及其相关的代谢紊乱。本研究旨在阐明脂肪细胞分泌蛋白SERPINA 3C在肥胖及相关代谢紊乱中的作用。雄性野生型（WT）和基因敲除（KO）小鼠用高脂饮食（HFD）喂养16周，评估肥胖、胰岛素抵抗和炎症。将AAV介导的SERPINA 3C过表达局部注射到腹股沟白色脂肪组织（iWAT）中以检查SERPINA 3C的作用。在3 T3-L1脂肪细胞中进行体外分析以探索SERPINA 3C功能的分子途径。SERPINA 3C基因敲除小鼠的功能研究表明，SERPINA 3C缺陷导致代谢表型受损（更严重的肥胖、更低的代谢率、更差的葡萄糖耐受不良和胰岛素不敏感性），这与白色脂肪组织的回升性炎症和细胞凋亡相关。与这些结果一致，腹股沟脂肪组织中SERPINA 3C的过表达保护小鼠免受饮食诱导的肥胖和代谢紊乱，脂肪组织中的炎症和细胞凋亡较少。在机制上，SERPINA 3C抑制组织蛋白酶G活性，作为丝氨酸蛋白酶抑制剂，其阻断组织蛋白酶G介导的α5/β1整联蛋白的转换。然后，α5/β1整联蛋白信号传导的保留完整性（增加）激活AKT以减少JNK磷酸化，从而抑制脂肪细胞中的炎症并促进胰岛素敏感性。这些发现证实了先前未知的SERPINA 3C/组织蛋白酶G/整合素/AKT通路在调节脂肪组织炎症中的作用，并表明靶向脂肪组织中的SERPINA 3C/组织蛋白酶G轴用于治疗肥胖和代谢性疾病的治疗潜力。SERPINA 3C缺失加重了HFD诱导的小鼠肥胖、胰岛素抵抗和炎症。iWAT中SERPINA 3C的过表达减轻了HFD诱导的肥胖、胰岛素抵抗和炎症。SERPINA 3C通过抑制组织蛋白酶G介导的整合素α5/β1的转换以激活AKT来减轻脂肪炎症。脂肪中的SERPINA 3C/Cathepsin G轴可能是2型糖尿病和肥胖的潜在治疗靶点。
Due to the increasing prevalence of obesity and insulin resistance, there is an urgent need for better treatment of obesity and its related metabolic disorders. This study aimed to elucidate the role of SERPINA3C, an adipocyte secreted protein, in obesity and related metabolic disorders. Male wild type (WT) and knockout (KO) mice were fed with high-fat diet (HFD) for 16 weeks, adiposity, insulin resistance, and inflammation were assessed. AAV-mediated overexpression of SERPINA3C was injected locally in inguinal white adipose tissue (iWAT) to examine the effect of SERPINA3C. In vitro analyses were conducted in 3T3-L1 adipocytes to explore the molecular pathways underlying the function of SERPINA3C. Functional exploration of the SERPINA3C knockout mice revealed that SERPINA3C deficiency led to an impaired metabolic phenotype (more severe obesity, lower metabolic rates, worse glucose intolerance and insulin insensitivity), which was associated with anabatic inflammation and apoptosis of white adipose tissues. Consistent with these results, overexpression of SERPINA3C in inguinal adipose tissue protected mice against diet-induced obesity and metabolic disorders with less inflammation and apoptosis in adipose tissue. Mechanistically, SERPINA3C inhibited Cathepsin G activity, acting as a serine protease inhibitor, which blocked Cathepsin G-mediated turnover of α5/β1 Integrin protein. Then, the preserved integrity (increase) of α5/β1 Integrin signaling activated AKT to decrease JNK phosphorylation, thereby inhibiting inflammation and promoting insulin sensitivity in adipocytes. These findings demonstrate a previously unknown SERPINA3C/Cathepsin G/Integrin/AKT pathway in regulating adipose tissue inflammation, and suggest the therapeutic potential of targeting SERPINA3C/Cathepsin G axis in adipose tissue for the treatment of obesity and metabolic diseases. SERPINA3C deletion aggravated HFD-induced obesity, insulin resistance and inflammation in mice. Overexpression of SERPINA3C in iWAT alleviated HFD-induced obesity, insulin resistance and inflammation. SERPINA3C relieved adipose inflammation by inhibiting Cathepsin G-mediated turnover of Integrin α5/β1 to activate AKT. The SERPINA3C/Cathepsin G axis in adipose might be a potential therapeutic target for type 2 diabetes and obesity.
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影响因子：
4.6
作者：
Kriszt R;Arai S;Itoh H;Lee MH;Goralczyk AG;Ang XM;Cypess AM;White AP;Shamsi F;Xue R;Lee JY;Lee SC;Hou Y;Kitaguchi T;Sudhaharan T;Ishiwata S;Lane EB;Chang YT;Tseng YH;Suzuki M;Raghunath M
通讯作者：
Raghunath M
影响因子：
12.3
作者：
Law RH;Zhang Q;McGowan S;Buckle AM;Silverman GA;Wong W;Rosado CJ;Langendorf CG;Pike RN;Bird PI;Whisstock JC
通讯作者：
Whisstock JC
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。
影响因子：
8.1
作者：
Bugler-Lamb AR;Hasib A;Weng X;Hennayake CK;Lin C;McCrimmon RJ;Stimson RH;Ashford MLJ;Wasserman DH;Kang L
通讯作者：
Kang L
牛磺酸介导的白色脂肪组织褐变与其对小鼠的抗肥胖作用有关
影响因子：
4.8
作者：
Guo, Ying-Ying;Li, Bai-Yu;Tang, Qi-Qun
通讯作者：
Tang, Qi-Qun
组织蛋白酶 G 裂解并激活 IL-36γ 并促进银屑病炎症
影响因子：
4.8
作者：
Guo, Jing;Tu, Jie;Yin, ZhiQiang
通讯作者：
Yin, ZhiQiang