Submitted to: Molecular Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/17/1998
Publication Date: N/A
Citation: Rosenbaum, S.E., Greenberg, A.S. 1998. The short- and long-term effects of tumor necrosis factor-alpha and brl 49653 on peroxisome proliferator-activated receptor (ppar) gamma-2 gene expression and other adipocyte genes. Molecular Endocrinology. 12(8):1150-60. Interpretive Summary: As people age and become more obese they develop insulin resistance, which is associated with an increased risk of developing heart disease, diabetes, and elevated blood lipids. Insulin resistance means that an individual's cells are more resistant to the actions of a given amount of insulin, the hormone that causes glucose to leave the blood and enter cells. Insulin resistance in obesity is associated with an increase in the production and secretion of the protein tumor necrosis factor-alpha (TNF) by fat cells. We tested whether a compound (BRL 49653) that is known to ameliorate insulin resistance in rats and obese humans counters the effects of TNF on insulin resistance. This study establishes a potential molecular pathway to understand how TNF leads to insulin resistance and how BRL 49653 ameliorates insulin resistance in aging, obese, and diabetic individuals.
Technical Abstract: Expression of tumor necrosis factor-alpha (TNF-alpha) in adipocytes has been reported to correlate with insulin resistance associated with obesity. The thiazolidinediones such as BRL 49653 have been reported to improve insulin sensitivity in obese animals and humans. Though its exact mechanism of action is not known, BRL 49653 has been shown to antagonize some of the inhibitory actions of TNF-alpha. BRL 49653 binds and activates the peroxisome proliferator activated receptor (PPAR-gamma-2), an important nuclear transcription factor in adipocyte differentiation; however its regulation of PPAR-gamma-2 in differentiated adipocytes is unknown. Prior reports have suggested that TNF-alpha decreases adipocyte gene expression by decreasing expression of PPAR-gamma-2. In this paper we find that BRL 49653 was unable to prevent TNF-alpha from downregulating PPAR-gamma-2 even though BRL 49653 blocked the ability of TNF-alpha to downregulate the expression and transcription of several adipocyte genes when it was coincubated with TNF-alpha. Moreover, BRL 49653 alone decreases the expression of PPAR-gamma-2 mRNA and protein in adipocytes and potentiates the downregulation of PPAR-gamma-2 mRNA by TNF-alpha. Using gel mobility shift assays, we incubated an oligonucleotide homologous to the PPAR-gamma-2/RXR-alpha heterodimer response element with nuclear extracts from TNF-alpha and/or BRL 49653 treated cells. The extracts from cells treated with BRL 49653 displayed an increase in specific protein/DNA complex suggesting that the thiazolidinediones exert their actions on differentiated adipocytes by increasing the association of PPAR-gamma-2 with its DNA response element.