ELEVATED EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA IN ADIPOSE-TISSUE FROM OBESE MICE

Background: Tumor necrosis factor-alpha (TNF-alpha) is chronically ele vated in the adipose tissue from obese humans and mice. This increase in TNF-alpha contributes to the insulin resistance, elevated plasminog en activator inhibitor-1 (PAI-1) levels, and cardiovascular complicati ons associated with obesity and noninsulin-dependent diabetes (NIDDM). PAI-1 gene expression in adipose tissue is also stimulated by transfo rming growth factor-beta (TGF-beta). Experiments were performed to det ermine whether TGF-beta is regulated by TNF-alpha and elevated in obes ity. Materials and Methods: The concentration of TGF-beta and PAI-1 mR NA in murine adipose tissue and cultured 3T3-L1 adipocytes was determi ned by quantitative reverse transcription polymerase chain reaction (R T-PCR), and the cellular localization of these molecules was evaluated using in situ hybridization and cell fractionation. Total TGF-beta pr otein was determined by employing an ELISA assay. Results: TGF-beta mR NA and protein were increased in the adipose tissue from two different strains of genetically obese mice (i.e., ob/ob and db/db), compared w ith their lean counterparts. This increase in TGF-beta may result from TNF-alpha since TNF-alpha increased TGF-beta mRNA expression in the a dipose tissue of lean mice and stimulated TGF-beta production by cultu red adipocytes. Administration of TGF-beta 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. Conclusions: TNF- alpha contributes to the elevated TGF-beta expression demonstrated in the adipose tissue of obese mice. A potential role for TGF-beta in the increased PAI-1 and vascular pathologies associated with obesity/NIDD M is suggested.