The branch point enzyme of the mevalonate pathway for protein prenylation is overexpressed in the ob/ob mouse and induced by adipogenesis

We have recently reported that skeletal muscle of the ob/ob mouse, an anima l model of genetic obesity with extreme insulin resistance, exhibits altera tions in the expression of multiple genes. Analysis and cloning of a full-l ength cDNA of one of the overexpressed mRNAs revealed a 300-amino-acid prot ein that could be identified as the mouse geranylgeranyl diphosphate syntha se (GGPP synthase) based on its homology to proteins cloned from yeast and fungus. GGPP synthase catalyzes the synthesis of all-trans-geranylgeranyl d iphosphate (GGPP), an isoprenoid used for protein isoprenylation in animal cells, and is a branch point enzyme in the mevalonic acid pathway. Three mR NAs for GGPP synthase of 4.3, 3.2, and 1.7 kb were detected in Northern blo t analysis. Western blot analysis of tissue homogenates using specific anti peptide antibodies revealed a single band of 34.8 kDa, Expression level of this protein in different tissues correlated with expression of the 4.3- an d 3.2-kb mRNAs. GGPP synthase mRNA expression was increased 5- to 20-fold i n skeletal muscle, liver, and fat of ob/ob mice by Northern blot analysis, Western blot analysis also showed a twofold overexpression of the protein i n muscle and fat but not in liver, where the dominant isoform is encoded by the 1.7-kb mRNA, Differentiation of 3T3-L1 fibroblasts into adipocytes ind uced GGPP synthase expression more than 20-fold, Using the immunoprecipitat ed protein, we found that mammalian GGPP synthase synthesizes not only GGPP but also its metabolic precursor farnesyl diphosphate, Thus, the expressio n of GGPP synthase is regulated in multiple tissues in obesity and is induc ed during adipocyte differentiation. Altered regulation in the synthesis of isoprenoids for protein prenylation in obesity might be a factor determini ng the ability of the cells to respond to hormonal stimulation requiring bo th Ras-related small GTPases and trimeric G protein-coupled receptors.