PDF(Pubmed)
Abstract：
BACKGROUND: White adipose tissue (WAT) has a key role in maintaining energy balance throughout the body, and their dysfunction take part in the regulation of diabetes mellitus. However, the internal regulatory mechanisms underlying are still unknown.
RESULTS: We generated adipocyte-specific FAK KO (FAK-AKO) mice and investigated their phenotype. The cascade of adipocyte, macrophage in adipocyte tissues, and pancreatic β-cells were proposed in FAK-AKO mice and validated by cell line studies using 3T3-L1, Raw264.7 and Min6. The FAK-AKO mice exhibited glucose intolerance, reduced adipose tissue mass and increased apoptosis, lipolysis and inflammatory response in adipose tissue. We further demonstrate that adipocyte FAK deletion increases β cell apoptosis and inflammatory infiltrates into islets, which is potentiated if mice were treated with STZ. In the STZ-induced diabetes model, FAK AKO mice exhibit less serum insulin content and pancreatic β cell area. Moreover, serum pro-inflammatory factors increased and insulin levels decreased after glucose stimulation in FAK AKO mice. In a parallel vitro experiment, knockdown or inhibition of FAK during differentiation also increased apoptosis, lipolysis and inflammatory in 3T3-L1 adipocytes, whereas the opposite was observed upon overexpression of FAK. Moreover, coculturing LPS-treated RAW264.7 macrophages with knockdown FAK of 3T3-L1 adipocytes increased macrophage pro-inflammatory response. Furthermore, conditioned medium from above stimulated Min6 cells apoptosis (with or without STZ), whereas the opposite was observed upon overexpression of FAK. Mechanistically, FAK protein interact with TRAF6 in adipocytes and knockdown or inhibition of FAK activated TRAF6/TAK1/NF-κB signaling, which exacerbates inflammation of adipocytes themselves.
CONCLUSIONS: Adipocyte FAK deletion promotes both adipocyte apoptosis and adipose tissue inflammation. Pro-inflammatory factors released by the FAK-null adipose tissue further trigger apoptosis in pancreatic islets induced by the administration of STZ, thereby exacerbating the diabetes mellitus. This study reveals a link between FAK-mediated adipose inflammation and diabetes mellitus, a mechanism that has not been previously recognized.
RESULTS: We generated adipocyte-specific FAK KO (FAK-AKO) mice and investigated their phenotype. The cascade of adipocyte, macrophage in adipocyte tissues, and pancreatic β-cells were proposed in FAK-AKO mice and validated by cell line studies using 3T3-L1, Raw264.7 and Min6. The FAK-AKO mice exhibited glucose intolerance, reduced adipose tissue mass and increased apoptosis, lipolysis and inflammatory response in adipose tissue. We further demonstrate that adipocyte FAK deletion increases β cell apoptosis and inflammatory infiltrates into islets, which is potentiated if mice were treated with STZ. In the STZ-induced diabetes model, FAK AKO mice exhibit less serum insulin content and pancreatic β cell area. Moreover, serum pro-inflammatory factors increased and insulin levels decreased after glucose stimulation in FAK AKO mice. In a parallel vitro experiment, knockdown or inhibition of FAK during differentiation also increased apoptosis, lipolysis and inflammatory in 3T3-L1 adipocytes, whereas the opposite was observed upon overexpression of FAK. Moreover, coculturing LPS-treated RAW264.7 macrophages with knockdown FAK of 3T3-L1 adipocytes increased macrophage pro-inflammatory response. Furthermore, conditioned medium from above stimulated Min6 cells apoptosis (with or without STZ), whereas the opposite was observed upon overexpression of FAK. Mechanistically, FAK protein interact with TRAF6 in adipocytes and knockdown or inhibition of FAK activated TRAF6/TAK1/NF-κB signaling, which exacerbates inflammation of adipocytes themselves.
CONCLUSIONS: Adipocyte FAK deletion promotes both adipocyte apoptosis and adipose tissue inflammation. Pro-inflammatory factors released by the FAK-null adipose tissue further trigger apoptosis in pancreatic islets induced by the administration of STZ, thereby exacerbating the diabetes mellitus. This study reveals a link between FAK-mediated adipose inflammation and diabetes mellitus, a mechanism that has not been previously recognized.
摘要：
背景：白色脂肪组织（WAT）在维持整个身体的能量平衡方面起着关键作用，它们的功能障碍参与了糖尿病的调节。然而,潜在的内部监管机制仍然未知。
结果:我们产生了脂肪细胞特异性FAKKO(FAK-AKO)小鼠并研究了它们的表型。脂肪细胞的级联，脂肪细胞组织中的巨噬细胞，在FAK-AKO小鼠中提出了胰腺β细胞，并通过使用3T3-L1，Raw264.7和Min6的细胞系研究进行了验证。FAK-AKO小鼠表现出葡萄糖耐受不良，脂肪组织质量减少，细胞凋亡增加，脂肪组织中的脂解和炎症反应。我们进一步证明，脂肪细胞FAK缺失增加β细胞凋亡和炎症浸润到胰岛，如果用STZ处理小鼠则增强。在STZ诱导的糖尿病模型中，FAKAKO小鼠表现出更低的血清胰岛素含量和胰腺β细胞面积。此外，糖刺激后FAKAKO小鼠血清促炎因子升高,胰岛素水平降低。在一个平行的体外实验中，分化过程中FAK的敲除或抑制也增加了细胞凋亡，3T3-L1脂肪细胞的脂解和炎症，而在FAK过表达时观察到相反的情况。此外，将LPS处理的RAW264.7巨噬细胞与3T3-L1脂肪细胞的FAK敲低共培养可增加巨噬细胞促炎反应。此外，来自上述刺激Min6细胞凋亡的条件培养基（有或没有STZ），而在FAK过表达时观察到相反的情况。机械上,FAK蛋白与脂肪细胞中的TRAF6相互作用，敲低或抑制FAK激活的TRAF6/TAK1/NF-κB信号，这加剧了脂肪细胞本身的炎症。
结论：脂肪细胞FAK缺失促进脂肪细胞凋亡和脂肪组织炎症。FAK空脂肪组织释放的促炎因子进一步触发STZ诱导的胰岛细胞凋亡，从而加剧糖尿病。这项研究揭示了FAK介导的脂肪炎症和糖尿病之间的联系，一种以前没有被认识到的机制。
结果:我们产生了脂肪细胞特异性FAKKO(FAK-AKO)小鼠并研究了它们的表型。脂肪细胞的级联，脂肪细胞组织中的巨噬细胞，在FAK-AKO小鼠中提出了胰腺β细胞，并通过使用3T3-L1，Raw264.7和Min6的细胞系研究进行了验证。FAK-AKO小鼠表现出葡萄糖耐受不良，脂肪组织质量减少，细胞凋亡增加，脂肪组织中的脂解和炎症反应。我们进一步证明，脂肪细胞FAK缺失增加β细胞凋亡和炎症浸润到胰岛，如果用STZ处理小鼠则增强。在STZ诱导的糖尿病模型中，FAKAKO小鼠表现出更低的血清胰岛素含量和胰腺β细胞面积。此外，糖刺激后FAKAKO小鼠血清促炎因子升高,胰岛素水平降低。在一个平行的体外实验中，分化过程中FAK的敲除或抑制也增加了细胞凋亡，3T3-L1脂肪细胞的脂解和炎症，而在FAK过表达时观察到相反的情况。此外，将LPS处理的RAW264.7巨噬细胞与3T3-L1脂肪细胞的FAK敲低共培养可增加巨噬细胞促炎反应。此外，来自上述刺激Min6细胞凋亡的条件培养基（有或没有STZ），而在FAK过表达时观察到相反的情况。机械上,FAK蛋白与脂肪细胞中的TRAF6相互作用，敲低或抑制FAK激活的TRAF6/TAK1/NF-κB信号，这加剧了脂肪细胞本身的炎症。
结论：脂肪细胞FAK缺失促进脂肪细胞凋亡和脂肪组织炎症。FAK空脂肪组织释放的促炎因子进一步触发STZ诱导的胰岛细胞凋亡，从而加剧糖尿病。这项研究揭示了FAK介导的脂肪炎症和糖尿病之间的联系，一种以前没有被认识到的机制。
