Laboratory of Health and Life Science, Graduate School of Health and Sports Science, Juntendo University, Inzai, Chiba 270-1695, Japan.
Department of Biomolecular Science, Institute of Biomedical Sciences, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan.
Int J Mol Sci. 2021 Feb 25;22(5):2293. doi: 10.3390/ijms22052293.
Differentiation-inducing factor-1 (DIF-1) is a chlorinated alkylphenone (a polyketide) found in the cellular slime mold . DIF-1 and its derivative, DIF-1(3M) promote glucose consumption in vitro in mammalian cells and in vivo in diabetic rats; they are expected to be the leading antiobesity and antidiabetes compounds. In this study, we investigated the mechanisms underlying the actions of DIF-1 and DIF-1(3M). In isolated mouse liver mitochondria, these compounds at 2-20 μM promoted oxygen consumption in a dose-dependent manner, suggesting that they act as mitochondrial uncouplers, whereas CP-DIF-1 (another derivative of DIF-1) at 10-20 μM had no effect. In confluent mouse 3T3-L1 fibroblasts, DIF-1 and DIF-1(3M) but not CP-DIF-1 induced phosphorylation (and therefore activation) of AMP kinase (AMPK) and promoted glucose consumption and metabolism. The DIF-induced glucose consumption was reduced by compound C (an AMPK inhibitor) or AMPK knock down. These data suggest that DIF-1 and DIF-1(3M) promote glucose uptake, at least in part, via an AMPK-dependent pathway in 3T3-L1 cells, whereas cellular metabolome analysis revealed that DIF-1 and DIF-1(3M) may act differently at least in part.
分化诱导因子-1（DIF-1）是一种氯化烷芳酮（聚酮），存在于细胞黏菌中。DIF-1及其衍生物 DIF-1(3M) 在体外促进哺乳动物细胞中的葡萄糖消耗，在糖尿病大鼠体内也有此作用；它们有望成为主要的抗肥胖和抗糖尿病化合物。在这项研究中，我们研究了 DIF-1 和 DIF-1(3M) 作用的机制。在分离的小鼠肝线粒体中，这些化合物在 2-20 μM 浓度下以剂量依赖性方式促进氧消耗，表明它们作为线粒体解偶联剂起作用，而 CP-DIF-1（DIF-1 的另一种衍生物）在 10-20 μM 浓度下没有作用。在汇合的小鼠 3T3-L1 成纤维细胞中，DIF-1 和 DIF-1(3M) 但不是 CP-DIF-1 诱导 AMP 激酶 (AMPK) 的磷酸化（因此激活），并促进葡萄糖消耗和代谢。DIF 诱导的葡萄糖消耗被化合物 C（AMPK 抑制剂）或 AMPK 敲低所减少。这些数据表明，DIF-1 和 DIF-1(3M) 通过 3T3-L1 细胞中的 AMPK 依赖途径促进葡萄糖摄取，至少部分如此，而细胞代谢组学分析表明，DIF-1 和 DIF-1(3M) 可能至少部分以不同的方式起作用。
