Echinomycin inhibits adipogenesis in 3T3-L1 cells in a HIF-independent manner

Abstract

Obesity is a risk factor for many diseases including diabetes, cancer, cardiovascular disease, and chronic kidney disease. Obesity is characterized by the expansion of white adipose tissue (WAT). Hypertrophy and hyperplasia of adipocytes cause tissue hypoxia followed by inflammation and fibrosis. Its trigger, preadipocyte differentiation into mature adipocytes, is finely regulated by transcription factors, signal molecules, and cofactors. We found that echinomycin, a potent HIF-1 inhibitor, completely inhibited adipogenesis in 3T3-L1 WAT preadipocytes by affecting the early phase of mitotic clonal expansion. The dose required to exert the effect was surprisingly low and the time was short. Interestingly, its inhibitory effect was independent of HIF-1 pathways. Time-course DNA microarray analysis of drug-treated and untreated preadipocytes extracted a major transcription factor, CCAAT/enhancer-protein β, as a key target of echinomycin. Echinomycin also inhibited adipogenesis and body weight gain in high fat diet mice. These findings highlight a novel role of echinomycin in suppressing adipocyte differentiation and offer a new therapeutic strategy against obesity and diabetes.

Retinoids Enhance the Expression of Cathelicidin Antimicrobial Peptide during Reactive Dermal Adipogenesis

“…This may suggest Camp transcription is entirely dependent on HIF1a or that the global effects of HIF1a further attenuate other mechanisms involved in the expression of Camp. Support for this comes from observations that HIF1a inhibition also downregulates Cebpb transcription and inhibits initiation of adipogenesis (45). Inhibition by acriflavine similarly downregulated Cebpb expression, whereas L-mimosine downregulated Cebpa, the latter of which has also been proposed to regulate CAMP expression.…”

Diabetes-induced glucolipotoxicity impairs wound healing ability of adipose-derived stem cells-through the miR-1248/CITED2/HIF-1α pathway

“…Overall, these data suggest that miR-1248 may restrain CITED2 under anoxic conditions, thus preventing angiogenesis dysfunction by promoting expression of angiogenesis growth factors in hADSCs. However, upregulated HIF-1α has been proved to promote AT fibrosis mainly through regulating gene expressions by encoding proteins involved in extracellular matrix remodeling and inflammation [65][66][67]. The focus of this study is stem cell therapy and wound healing, deposition and remodeling of extracellular matrix are beneficial for AGING wound healing.…”

Insights into DNA‐drug interactions in the era of omics

“…[43] Furthermore, it inhibits adipogenesis in 3 T3-L1 white adipose tissue cells in a HIF-independent way. [44] In this case, the CCAAT/enhancerprotein β transcription factor is a key target of echinomycin. [44] In a mouse model of relapsed acute myeloid leukemia (AML), echinomycin protects mice against relapsed AML without impairing normal hematopoiesis.…”