Beskrivning
AMPK activation constitutes a strategy for the treatment of type 2 diabetes due to its beneficial effects in liver and muscle. In adipocytes, the effect of AMPK activation is less clear and previous studies mainly employed AICAR – a compound with limited specificity. Activators of the new generation are more specific and include A769662 and 991, which both bind the AMPK beta subunit but with different preference for the different beta isoforms. Based on the use of AICAR, as well as genetic mouse models, it is believed that AMPK activation causes a decrease in lipolysis via the phosphorylation of hormone-sensitive lipase (HSL) on an inhibitory site, S565, which is thought to counteract the activating PKA phosphorylation on for example S563. The aim of this study was to re-evaluate the role of AMPK in the regulation of adipocyte lipolysis with the direct AMPK activators A769662 and 991 with respect to different species including the characterization of AMPK subunit expression in the respective model. While mouse and rat cells are commonly used we aimed at the additional investigation of human cells. In line with the model described above, A769662 was, similar to AICAR, shown to cause a reduction in catecholamine induced lipolysis in primary mouse adipocytes, and this was accompanied by an increase in HSL S565 phosphorylation and reduction in S563 phosphorylation. However, in primary human- and rat adipocytes, A769662 in fact increased lipolysis. Moreover, AMPK activation by 991 in human- and rat adipocytes did not display an anti-lipolytic effect. Interestingly, although 991 did not affect lipolysis in human adipocytes, it induced a decrease in HSL S563 and increase in S565 phosphorylation, respectively. Potential effects on ATGL and/or perilipin, which could compensate for the HSL inactivation by 991, are under investigation. Analysis of the isoform prevalence in the used models revealed a significantly lower AMPK beta2 expression, relative that of beta1, in rat- compared to human and mouse adipocytes. Our data suggests that some of the effects of AICAR on adipocyte lipolysis in rat and human adipocytes might be AMPKindependent. Additionally, the data suggests differential regulation of lipolytic proteins in primary rat and human adipocytes.| Period | 2017 sep. 11 |
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| Evenemangstitel | 3rd European Workshop on AMPK |
| Typ av evenemang | Konferens |
| Plats | FrankrikeVisa på karta |
| Omfattning | Internationell |