College of Medicine, University of Ulsan, Gangneung Asan Hospital, Gangneung, 25440, Republic of Korea.
Food Microbiology Division, Ministry of Food and Drug Safety, Cheongju, 363-700, Republic of Korea.
Biochem Biophys Res Commun. 2019 Mar 19;510(4):621-628. doi: 10.1016/j.bbrc.2019.02.013. Epub 2019 Feb 8.
Previous reports have shown that PPARβ/δ agonists ameliorate insulin resistance associated with type 2 diabetes mellitus (T2DM). To determine the role of PPARβ/δ in tumor necrosis factor α (TNFα)-mediated insulin resistance, we investigated expression levels of adiponectin and insulin receptor (IR) in response to treatment with the PPARβ/δ agonist GW501516 with or without TNFα, a proinflammatory cytokine, in differentiated 3T3-L1 adipocytes. GW501516 induced adipocyte differentiation and the expression of adiponectin in a dose-dependent manner in differentiated adipocytes. TNFα treatment reduced adiponectin expression at the end of differentiation. This effect was reversed by GW501516 co-treatment with TNFα. TNFα treatment decreased adipogenic marker genes such as PPARγ, aP2, resistin, and GLUT4, and GW501516 reversed the effects of TNFα. GW501516 treatment increased the expression of insulin receptor and inhibited TNFα-mediated repression of insulin receptor. Our results showed that GW501516 abrogated TNFα-induced insulin resistance. In summary, our study demonstrated that the PPARβ/δ agonist, GW501516 reversed TNFα-induced decreases in adipocyte differentiation and adiponectin expression, and improved insulin sensitivity by increasing the expression of insulin receptor. Therefore, PPARδ may be a promising therapeutic target for treatment of insulin resistance in patients with T2DM.
先前的报告表明，过氧化物酶体增殖物激活受体β/δ（PPARβ/δ）激动剂可改善 2 型糖尿病（T2DM）相关的胰岛素抵抗。为了确定 PPARβ/δ 在肿瘤坏死因子α（TNFα）介导的胰岛素抵抗中的作用，我们研究了在分化的 3T3-L1 脂肪细胞中，用或不用 TNFα（一种促炎细胞因子）处理 PPARβ/δ 激动剂 GW501516 时，脂联素和胰岛素受体（IR）的表达水平。GW501516 以剂量依赖的方式诱导脂肪细胞分化和脂联素的表达。TNFα 处理在分化结束时降低了脂联素的表达。这种作用可被 GW501516 与 TNFα 共同处理逆转。TNFα 处理降低了脂肪生成标志物基因的表达，如过氧化物酶体增殖物激活受体γ（PPARγ）、脂肪型脂肪酸结合蛋白（aP2）、抵抗素和葡萄糖转运蛋白 4（GLUT4），而 GW501516 逆转了 TNFα 的作用。GW501516 处理增加了胰岛素受体的表达，并抑制了 TNFα 介导的胰岛素受体抑制。我们的结果表明，GW501516 阻断了 TNFα 诱导的胰岛素抵抗。综上所述，我们的研究表明，PPARβ/δ 激动剂 GW501516 逆转了 TNFα 诱导的脂肪细胞分化和脂联素表达降低，并通过增加胰岛素受体的表达改善了胰岛素敏感性。因此，PPARδ 可能是治疗 T2DM 患者胰岛素抵抗的有前途的治疗靶点。
