Exploring the Importance of PREX Proteins in Glucose Homeostasis and Insulin Signalling
PREX protein family (PREX1 and PREX2) guanine-nucleotide exchange factors (GEFs) activate the small G protein Rac. They are important in many physiological and pathophysiological processes, including inflammation, neuronal plasticity, cancer progression and metastasis, with an exciting new role in metabolic processes currently emerging. PREX1 was shown to regulate the thermogenic capacity and insulin-stimulated glucose uptake in adipocytes, whereas PREX2 was reported to mediate glucose tolerance, possibly through its adaptor function as an inhibitor of the tumour suppressor PTEN. The aims of this project were to explore the importance of PREX proteins in glucose homeostasis and insulin signalling, and to assess the significance of PREX Rac-GEF activity in these processes. Western blotting showed that both Prex proteins are expressed in brain, liver and brown adipose tissue, whereas Prex1 is also expressed white adipose tissue. Prex1 deficient mice had small livers, with reduced glycogen storage, eosinophilia in brown adipose tissue and reduced fasting plasma levels of adiponectin. Surprisingly, Prex1 deficiency lowered fasting blood glucose levels and protected mice from age-related glucose intolerance, in a diet- and sex-dependent manner. Bone marrow transplantation revealed that hematopoietic Prex1 deficiency was sufficient for the improved glucose tolerance. In contrast, Prex2 deficiency only affected glucose homeostasis in mice on high-fat diet, causing glucose intolerance and insulin resistance in old age. The phenotype of Prex1/Prex2 double-deficient mice suggested limited sex- and diet-dependent redundancy between both Prex proteins, as well as compensation by other regulators of glucose homeostasis. Overexpression of wild type or catalytically-inactive PREX1 and PREX2 in HepG2 cells caused increased insulin-stimulated Akt activity, suggesting that both PREX proteins can mediate insulin signalling at least in part through adaptor functions. Therefore, catalytically-inactive Prex1 and Prex2 mouse strains were generated and the metabolic phenotype of the catalytically-inactive Prex2 strain was assessed. In contrast to the Prex2 KO mice, catalytically-inactive Prex2 mice had reduced fasting blood glucose levels and improved glucose tolerance, both on chow and high fat diet. Taken together, these finding indicate that Prex1 and Prex2 have unexpected, important and divergent physiological roles in the regulation of glucose homeostasis, and that some of these roles are through adaptor functions. My work suggests that the development of therapeutics to target PREX activity may be a new avenue for the treatment of metabolic syndrome.
PREX, GEF, Glucose metabolism, Insulin signalling
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