AQP7 Mediates Post-Menopausal Lipogenesis in Adipocytes Through FSH-induced Transcriptional Crosstalk with AP-1 Sites

Research question: Fat accumulation is present in most post-menopausal women, but the underlying mechanism remains unclear. Aquaporin 7 (AQP7) is the most important glycerol channel facilitating glycerol efflux in adipocytes. High circulating FSH in post-menopausal women may play an independent role in regulation of the lipogenic effect of AQP7 in adipocytes. This study explored the role of AQP7 in the pathophysiology of post-menopausal lipogenesis mediated by high concentrations of circulating FSH. Design: Primary adipocytes from post-menopausal and childbearing women were analysed. An in-vivo postmenopausal animal model was established. AQP7 expression, lipid accumulation and glycerol concentration in adipocytes were measured. Luciferase reporter assay and chromatin immunoprecipitation were performed to identify transcriptional crosstalk in AQP7 promoter. Results: It was found that FSH down-regulated AQP7 expression and glycerol efflux function in mature adipocytes of post-menopausal women and ovariectomized (OVX) mice. In vitro, FSH inhibited lipid accumulation in primary cultured mature adipocytes in a dose-dependent manner and the mechanism was down-regulating AQP7 expression via a FSH receptor pathway. The effect of FSH on AQP7 in adipocytes was through activation of cAMP response element-binding (CREB) protein, which could bind to activator protein-1 (AP-1) sites in the AQP7 promoter, and therefore inhibited the transcriptional activation elicited by c-Jun. Conclusions: Down-regulation of AQP7 by FSH mediated post-menopausal lipogenesis, and the role of FSH was based on binding competition for AP-1 sites between CREB and c-Jun.