Bilirubin Increases Insulin Sensitivity in Leptin-Receptor Deficient and Diet-Induced Obese Mice Through Suppression of ER Stress and Chronic Inflammation
Bilirubin Increases Insulin Sensitivity in Leptin-Receptor Deficient and Diet-Induced Obese Mice Through Suppression of ER Stress and Chronic Inflammation
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DOI：
10.1210/en.2013-1667
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发表时间：
2014-03-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Hongjun
中科院分区：
文献类型：
--
作者：
Dong, Huansheng;Huang, Hu;Wang, Hongjun
肥胖诱导的内质网（ER）应激引起脂肪组织中的慢性炎症和肝脏中的脂肪变性，并最终导致胰岛素抵抗和2型糖尿病（T2 D）。本研究的目的是了解胆红素（一种强有力的抗氧化剂）降低瘦素受体缺陷（db/db）和饮食诱导肥胖（DIO）小鼠高血糖和改善肥胖的机制。db/db或DIO小鼠用胆红素或媒介物ip注射。测量血糖和体重。在小鼠的骨骼肌、脂肪组织和肝脏中测量胰岛素信号通路的活化、炎性细胞因子的表达和ER应激标记物。胆红素给药显著降低db/db小鼠的高血糖症并增加胰岛素敏感性。胆红素处理增加骨骼肌中蛋白激酶B（PK B/Akt）磷酸化，抑制ER应激标志物的表达，包括78 kDa葡萄糖调节蛋白（GRP 78）、CCAAT/增强子结合蛋白（C/EBP）同源蛋白、X盒结合蛋白（XBP-1）和db/db小鼠中转录激活因子4。在DIO小鼠中，胆红素治疗显著降低体重并增加胰岛素敏感性。此外，胆红素抑制脂肪组织中的巨噬细胞浸润和促炎细胞因子表达，包括TNF-α、IL-1 β和单核细胞趋化蛋白-1。在DIO小鼠的肝脏和脂肪组织中，胆红素改善肝脏脂肪变性，并降低GRP 78和C/EBP同源蛋白的表达。这些结果表明，在基因工程小鼠模型和DIO小鼠模型中，胆红素给药通过增加胰岛素敏感性来改善高血糖和肥胖。基于其深刻的抗ER应激和抗炎特性，胆红素或增加胆红素的药物可能可用作胰岛素增敏剂，用于治疗肥胖诱导的胰岛素抵抗和2型糖尿病。
Obesity-induced endoplasmic reticulum (ER) stress causes chronic inflammation in adipose tissue and steatosis in the liver, and eventually leads to insulin resistance and type 2 diabetes (T2D). The goal of this study was to understand the mechanisms by which administration of bilirubin, a powerful antioxidant, reduces hyperglycemia and ameliorates obesity in leptin-receptor-deficient (db/db) anddiet-induced obese (DIO) mousemodels. db/db or DIO mice were injected with bilirubin or vehicle ip. Blood glucose and body weight were measured. Activation of insulin-signaling pathways, expression of inflammatory cytokines, and ER stress markers were measured in skeletal muscle, adipose tissue, and liver of mice. Bilirubin administration significantly reduced hyperglycemia and increased insulin sensitivity in db/db mice. Bilirubin treatment increased protein kinase B (PKB/Akt) phosphorylation in skeletal muscle and suppressed expression of ER stress markers, including the 78-kDa glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein, X box binding protein (XBP-1), and activating transcription factor 4 in db/db mice. In DIO mice, bilirubin treatment significantly reduced body weight and increased insulin sensitivity. Moreover, bilirubin suppressed macrophage infiltration and proinflammatory cytokine expression, including TNF-alpha, IL-1 beta, and monocyte chemoattractant protein-1, in adipose tissue. In liver and adipose tissue of DIO mice, bilirubin ameliorated hepatic steatosis and reduced expression of GRP78 and C/EBP homologous protein. These results demonstrate that bilirubin administration improves hyperglycemia and obesity by increasing insulin sensitivity in both genetically engineered and DIO mice models. Bilirubin or bilirubin-increasing drugs might be useful as an insulin sensitizer for the treatment of obesity-induced insulin resistance and type 2 diabetes based on its profound anti-ER stress and antiinflammatory properties.