Endocrine Abstracts

In adipose tissue, estrogens are synthesized in the mesenchymal preadipocyte cells. This arises because aromatase, the enzyme responsible for estrogen biosynthesis is located in these cells as distinct from differentiated adipocytes. Regulation of aromatase expression in these cells is primarily due to a distal promoter, promoter I.4. Differentation of preadipocytes to the lipid-laden phenotype results in loss of aromatase transcripts coincident with increased PPARgamma expression. Consistent with this, PPARgamma ligands inhibit aromatase expression, and class I cytokines, TNFalpha and PGE2, all of which inhibit adipocyte differentiation or stimulate lipolysis, stimulate aromatase expression. Complete estrogen deficiency in humans and mice leads to abdominal adiposity, hepatic steatosis, and insulin resistance. Thus estrogen must be considered along with leptin, adiponectin, resistin and cortisol as an adipose-derived hormone that regulates adiposity. The relative importance of peripheral versus central actions, however, remains to be ascertained. In the presence of a breast tumor, aromatase expression in breast preadipocytes is driven primarily by the proximal gonadal promoter II. In the ovary, expression from this promoter requires the monomeric orphan nuclear receptor, SF-1. However SF-1 is not expressed in adipose tissue. Instead, LRH-1 is expressed in preadipocytes and breast tumors and is as effective as SF-1 in stimulating aromatase expression. LRH-1 expression declines markedly upon initiation of adipose differentiation, preceding the decline in aromatase expression. Thus LRH-1 is a major factor regulating estrogen biosynthesis in breast adipose tissue and may also be a novel factor in the regulation of adipocyte differentiation. In post-menopausal women the source of estrogen most implicated in breast tumor development is local synthesis. Hence LRH-1 could be a target for development of new drugs for breast cancer therapy.