Tumor necrosis factor-α (TNF-α) is chronically elevated in the adipose tissue from obese humans and mice. This increase in TNF-α contributes to the insulin resistance, elevated plasminogen activator inhibitor-1 (PAI-1) levels, and cardiovascular complications associated with obesity and noninsulin-dependent diabetes (NIDDM). PAI-1 gene expression in adipose tissue is also stimulated by transforming growth factor-β (TGF-β). Experiments were performed to determine whether TGF-β is regulated by TNF-α and elevated in obesity.

The concentration of TGF-β and PAI-1 mRNA in murine adipose tissue and cultured 3T3-L1 adipocytes was determined by quantitative reverse transcription polymerase chain reaction (RT-PCR), and the cellular localization of these molecules was evaluated using in situ hybridization and cell fractionation. Total TGF-β protein was determined by employing an ELISA assay.

TGF-β mRNA and protein were increased in the adipose tissue from two different strains of genetically obese mice (i.e., ob/ob and db/db), compared with their lean counterparts. This increase in TGF-β may result from TNF-α since TNF-α increased TGF-β mRNA expression in the adipose tissue of lean mice and stimulated TGF-β production by cultured adipocytes. Administration of TGF-β increased PAI-1 antigen in the plasma and PAI-1 mRNA in the adipocytes of lean mice, and enhanced the rate of PAI-1 synthesis by adipocytes in vitro.

TNF-α contributes to the elevated TGF-β expression demonstrated in the adipose tissue of obese mice. A potential role for TGF-β in the increased PAI-1 and vascular pathologies associated with obesity/NIDDM is suggested.