ROLE OF CALPAIN ON THE DIFFERENTIATION AND FUNCTION OF ADIPOCYTES

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Calpain is a calcium-activated non-lysosomal neutral thiol protease (EC 3.4.22.17) present in a wide variety of eukaryotic cells. Calpain is usually present as an inactive form and is activated by calcium ions and phospholipids. The activity of calpain is required during the mitotic clonal expansion phase of 3T3-L1 preadipocyte differentiation. We addressed that blocking calpain activity enhances the adipogenesis of adult primitive mesenchymal ST-13 preadipocytes, the differentiation of which using standard hormones does not require mitotic clonal expansion. We also examined whether a calpain blockade induces insulin resistance in mature ST-13 adipocytes. Exposing ST-13 preadipocytes to the calpain inhibitor, N-benzyloxycarbonyl-L-leucyl-L-leucinal or to the overexpression of calpastatin, a specific endogenous inhibitor of calpain, stimulated acquisition of the adipocyte phenotype. Overexpression of calpastatin in ST-13 adipocytes stimulated the expression of the adipocyte-specific CCAAT/enhancer-binding protein a (C/EBP α), peroxisome proliferator-activated receptor γ (PPARγ), sterol regulatory element-binding protein 1 (SREBP-1) and the insulin signaling molecules, insulin receptor α, insulin-receptor substrates and GLUT4. However, insulin-stimulated glucose uptake was reduced by approximately 52%. These results suggest that calpain negatively regulates adipogenesis in adult primitive mesenchymal ST-13 preadipocytes in contrast to that of embryonic 3T3-L1 preadipocytes and is required for the insulin-stimulated glucose uptake in mature ST-13 adipocytes.