Vigueira Patrick A, McCommis Kyle S, Hodges Wesley T, Schweitzer George G, Cole Serena L, Oonthonpan Lalita, Taylor Eric B, McDonald William G, Kletzien Rolf F, Colca Jerry R, Finck Brian N
Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USA.
Metabolic Solutions Development Company, Kalamazoo, MI, 49007, USA.
Exp Physiol. 2017 Aug 1;102(8):985-999. doi: 10.1113/EP086380. Epub 2017 Jul 10.
What is the central question of this study? The antidiabetic effects of thiazolidinedione (TZD) drugs may be mediated in part by a molecular interaction with the constituent proteins of the mitochondrial pyruvate carrier complex (MPC1 and MPC2). We examined the ability of a mutant mouse strain expressing an N-terminal truncation of MPC2 (Mpc2Δ16 mice) to respond to TZD treatment. What is the main finding and its importance? The response of Mpc2Δ16 mice to TZD treatment was not significantly different from that of wild-type C57BL6/J control animals, suggesting that the 16 N-terminal amino acids of MPC2 are dispensable for the effects of TZD treatment. Rosiglitazone and pioglitazone are thiazolidinedione (TZD) compounds that have been used clinically as insulin-sensitizing drugs and are generally believed to mediate their effects via activation of the peroxisome proliferator-activated receptor γ (PPARγ). Recent work has shown that it is possible to synthesize TZD compounds with potent insulin-sensitizing effects and markedly diminished affinity for PPARγ. Both clinically used TZDs and investigational PPARγ-sparing TZDs, such as MSDC-0602, interact with the mitochondrial pyruvate carrier (MPC) and inhibit its activity. The MPC complex is composed of two proteins, MPC1 and MPC2. Herein, we used mice expressing a hypomorphic MPC2 protein missing 16 amino acids in the N-terminus (Mpc2Δ16 mice) to determine the effects of these residues in mediating the insulin-sensitizing effects of TZDs in diet-induced obese mice. We found that both pioglitazone and MSDC-0602 elicited their beneficial metabolic effects, including improvement in glucose tolerance, attenuation of hepatic steatosis, reduction of adipose tissue inflammation and stimulation of adipocyte browning, in both wild-type and Mpc2Δ16 mice after high-fat diet feeding. In addition, truncation of MPC2 failed to attenuate the interaction between TZDs and the MPC in a bioluminescence resonance energy transfer-based assay or to affect the suppression of pyruvate-stimulated respiration in cells. Collectively, these data suggest that the interaction between TZDs and MPC2 is not affected by loss of the N-terminal 16 amino acids nor are these residues required for the insulin-sensitizing effects of these compounds.
本研究的核心问题是什么？噻唑烷二酮（TZD）类药物的抗糖尿病作用可能部分是通过与线粒体丙酮酸载体复合物（MPC1和MPC2）的组成蛋白发生分子相互作用来介导的。我们检测了表达MPC2 N端截短体的突变小鼠品系（Mpc2Δ16小鼠）对TZD治疗的反应能力。主要发现及其重要性是什么？Mpc2Δ16小鼠对TZD治疗的反应与野生型C57BL6/J对照动物没有显著差异，这表明MPC2的16个N端氨基酸对于TZD治疗的效果是可有可无的。罗格列酮和吡格列酮是噻唑烷二酮（TZD）类化合物，临床上用作胰岛素增敏药物，一般认为它们通过激活过氧化物酶体增殖物激活受体γ（PPARγ）来介导其作用。最近的研究表明，有可能合成具有强效胰岛素增敏作用且对PPARγ亲和力显著降低的TZD化合物。临床上使用的TZD类药物和研究中的PPARγ选择性TZD类药物，如MSDC-0602，都与线粒体丙酮酸载体（MPC）相互作用并抑制其活性。MPC复合物由两种蛋白质MPC1和MPC2组成。在此，我们使用在N端缺失16个氨基酸的低表达MPC2蛋白的小鼠（Mpc2Δ16小鼠）来确定这些残基在介导TZD类药物对饮食诱导肥胖小鼠的胰岛素增敏作用中的影响。我们发现，在高脂饮食喂养后，吡格列酮和MSDC-0602在野生型和Mpc2Δ16小鼠中均产生了有益的代谢作用，包括改善糖耐量、减轻肝脏脂肪变性、减轻脂肪组织炎症以及刺激脂肪细胞褐变。此外，在基于生物发光共振能量转移的实验中，MPC2的截短并未减弱TZD类药物与MPC之间的相互作用，也未影响对细胞中丙酮酸刺激的呼吸作用的抑制。总的来说，这些数据表明，TZD类药物与MPC2之间的相互作用不受N端16个氨基酸缺失的影响，这些残基对于这些化合物的胰岛素增敏作用也不是必需的。
