Arthrocolin B Impairs Adipogenesis via Delaying Cell Cycle Progression During the Mitotic Clonal Expansion Period

TL;DR

Arthrocolin B stops fat cell development by slowing down cell cycle progression during a key growth phase, which could help treat obesity.

Contribution

Arthrocolin B's novel role in inhibiting adipogenesis via cell cycle modulation during mitotic clonal expansion is revealed.

Findings

Arthrocolin B reduces lipid accumulation and downregulates key adipogenesis factors like SREBP1 and PPARγ.

It causes cell cycle arrest during MCE by modulating p53, AKT, and ERK pathways and altering CDK and cyclin expression.

Arthrocolin B promotes CPT1A expression, suggesting a role in fatty acid oxidation during adipocyte differentiation.

Abstract

Obesity and its related diseases severely threaten people’s health, causing persistently high morbidity and mortality worldwide. The abnormal proliferation and hypertrophy of adipocytes mediate the expansion of adipose tissue, which is the main cause of obesity-related diseases. Inhibition of cell proliferation during the mitotic clonal expansion (MCE) period of adipogenesis may be a promising strategy for preventing and treating obesity. Arthrocolins are a series of fluorescent dye-like complex xanthenes from engineered Escherichia coli, with potential anti-tumor and antifungal activities. However, the role and underlying mechanisms of these compounds in adipocyte differentiation remain unclear. In this study, we discovered that arthrocolin B, a member of the arthrocolin family, significantly impeded adipogenesis by preventing the accumulation of lipid droplets and triglycerides, as well as by downregulating the expression of key factors involved in adipogenesis, such as SREBP1, C/EBPβ, C/EBPδ, C/EBPα, PPARγ, and FABP4. Moreover, we revealed that this inhibition might be a consequence of cell cycle arrest during the MCE of adipocyte differentiation, most likely by modulating the p53, AKT, and ERK pathways, upregulating the expression of p21 and p27, and repressing the expression of CDK1, CDK4, Cyclin A2, Cyclin D1, and p-Rb. Additionally, arthrocolin B could promote the expression of CPT1A during adipocyte differentiation, implying its potential role in fatty acid oxidation. Overall, our research concludes that arthrocolin B has the ability to suppress the early stages of adipocyte differentiation mainly by modulating the signaling proteins involved in cell cycle progression. This work broadens our understanding of the function and mechanisms of arthrocolins in regulation of adipogenesis and might provide a potential lead compound for treating the obesity.

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