Regulation of metallothionein gene expression and secretion in rat adipocytes differentiated from preadipocytes in primary culture

The gene encoding metallothionein, a low mel. wt. metal binding and stress response protein, is expressed in white adipose tissue. In the present stud y, metallothionein (MT-1) gene expression and factors regulating metallothi onein production have been examined in adipocytes induced to differentiate from fibroblastic preadipocytes in primary cell culture. On the induction o f differentiation, the metallothionein-1 gene was strongly expressed in the cells and metallothionein released into the medium. A peak in metallothion ein-1 mRNA level and metallothionein secretion occurred at 2 and 10 days po st-differentiation, respectively, with a decrease in protein release after this time. The metallothionein-1 gene was expressed in the adipocytes prior to the adipsin and lipoprotein lipase genes, suggesting that it is an earl y marker of adipocyte differentiation. The addition of the glucocorticoid. dexamethasone, led to a substantial increase in metallothionein-1 mRNA in t he cells and metallothionein secretion. Insulin and leptin also stimulated metallothionein production, although the effect was small. Neither noradren aline nor the beta3-adrenoceptor agonist, BRL 37 344, altered metallothione in release but forskolin and bromo-cAMP were stimulatory, markedly increasi ng both metallothionein-1 level and metallothionein secretion. It is sugges ted that metallothionein is a novel secretory product of the differentiated white adipocyte and that its production is regulated particularly by gluco corticoids and through a cAMP-dependent pathway.