Anchoring disruption as therapeutic strategy for regulation of beta-adrenergic signalling in adipose-tissue and prostaglandin signalling in

Specificity of cAMP/PKA signalling is achieved by the subcellular localization of PKA. PKA can be localized to different subcellular structures by targeting to anchoring proteins - AKAPs. In vitro, functional conxequences have been studied by over-express ing soluble AKAPs that contain a PKA binding site and in this way manipulate the subcellular distribution of PKA. However, such anchoring disrupters have never been expressed in living animals. We would like to investigate the role of AKAPs in vivo, by de veloping transgenic mice that over-express soluble AKAP fragments under control of various-tissue specific promoters. Obesity and insulin resistance are common forerunners of diabetes type II. Recently we have identified the transcription factor FOXC2 as a key regulator of adipocyte metabolism (Cederberg et al., Cell, 2001). FOXC2 affects adipocyte metabolism by increasing the senxitivity of the beta-adrenergic-cAMP-protein kinase A (PKA) signalling via up-regulation of PKA-RIa in whi t in kinase A (PKA) signalling via up-regulation of PKA-RIa in whi