Dictyostelium Differentiation-Inducing Factor-1 Promotes Glucose Uptake, at Least in Part, via an AMPK-Dependent Pathway in Mouse 3T3-L1 Cells.

Yuzuru Kubohara,Hiroshi Shibata,Haruhisa Kikuchi,Yoshimi Homma,Yoshiteru Oshima

doi:10.3390/ijms22052293

Abstract

Differentiation-inducing factor-1 (DIF-1) is a chlorinated alkylphenone (a polyketide) found in the cellular slime mold Dictyostelium discoideum. 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.

Highlights

The cellular slime mold Dictyostelium discoideum is an excellent model organism for cell and developmental biology; at the end of its development, it forms fruiting bodies, each consisting of spores and a multicellular stalk [1,2]
Twenty years after the discovery of Differentiation-inducing factor-1 (DIF-1), we coincidentally found that DIF-1 can promote glucose consumption in mammalian cells, such as mouse 3T3-L1 fibroblasts and 3T3-L1 adipocytes [21]
We have previously shown that DIF-3 and some of its derivatives might function, at least in part, by promoting mitochondrial oxygen consumption (MOC) by uncoupling mitochondrial activity elucidate theefficient mechanism of the glucose uptake-promoting activities of and DIF-1 (3M)Towas more than

Summary

Introduction

The cellular slime mold Dictyostelium discoideum is an excellent model organism for cell and developmental biology; at the end of its development, it forms fruiting bodies, each consisting of spores and a multicellular stalk [1,2]. (DIF-1) (Figure 1A), a chlorinated alkylphenone (a polyketide), functions as an inducer of stalk cell differentiation and as a modulator of chemotactic cell movement in the development of D. discoideum [3,4,5,6]. Twenty years after the discovery of DIF-1, we coincidentally found that DIF-1 can promote glucose consumption in mammalian cells, such as mouse 3T3-L1 fibroblasts (preadipocytes and a model of non-transformed cells) and 3T3-L1 adipocytes [21]. DIF1 induces translocation of glucose transporter 1 (GLUT1) from intracellular vesicles to

Methods

Results

Conclusion