Abstract
Geldanamycin derivatives are benzoquinone ansamycin antibiotics that bind to Hsp90 and alter its function. The alteration of Hsp90 activity limits some cellular hormonal responses by inhibiting nuclear receptors activation. The nuclear receptors activity, such as PPARγ, the mineralocorticoid and glucocorticoid receptors (MR and GR) play a critical role in the conversion of preadipocytes to mature adipocytes. Given the importance of these nuclear receptors for adipogenesis, we investigated the effects of geldanamycin analogues (GA) on adipocyte differentiation and function. We found that early exposure of preadipocyte cells to GA inhibited their conversion into mature adipocytes by inhibiting the adipogenic transcriptional program and lipid droplets accumulation. Furthermore, GA altered the adipokines secretion profile of mature adipocyte. The anti-adipogenic effect of GA was also confirmed in mice fed a high fat diet. Biochemical analysis revealed that anti-adipogenic effects of geldanamycin analogues may result from the simultaneous inhibition of MR, GR and PPARγ activity. Taken together, our observations lead us to propose Hsp90 as a potent target for drug development in the control of obesity and its related metabolic complications.
Highlights
Adipogenesis represents the complex cascade of events leading a preadipocyte to acquire the feature of a mature adipocyte
Given the determinant role of nuclear receptors in adipogenesis, we investigated the effects of two geldanamycin analogues, the DMSO soluble 17-AAG and the water soluble 17-DMAG on adipogenesis
We showed that geldanamycin analogues prevented adipocyte differentiation by inhibiting the adipogenic transcriptional program that led to the reduction of lipid accumulation into the cell
Summary
Adipogenesis represents the complex cascade of events leading a preadipocyte to acquire the feature of a mature adipocyte. It occurs as a consequence of normal cell turnover, and contribute to adipose tissue expansion in response to hormonal cues and calorie surplus [1]. Excess adipocyte size or number leads to obesity, which is a hallmark of metabolic syndrome (MetS) that includes hypertension, diabetes and dyslipidemia [2]. Obesity affects around 300 million individuals worldwide, a number that is expected to grow continuously in the years, making obesity and MetS a priority in health expenses [3]. This cascade will maintain the expression of these critical transcription factors thanks to a positive feedback loop where C/EBPa and PPARc reciprocally reinforce their expression [4]
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