TUMOR-NECROSIS-FACTOR-ALPHA CONTRIBUTES TO OBESITY-RELATED HYPERLEPTINEMIA BY REGULATING LEPTIN RELEASE FROM ADIPOCYTES

Cytokines, in particular tumor necrosis factor-alpha (TNF-alpha), have significant effects on energy metabolism and appetite although their mechanisms of action are largely unknown. Here, we examined whether TN F-alpha modulates the production of leptin, the recently identified fa t-specific energy balance hormone, in cultured adipocytes and in mice. TNF-alpha treatment of 3T3-L1 adipocytes resulted in rapid stimulatio n of leptin accumulation in the media, with a maximum effect at 6 h, T his stimulation was insensitive to cycloheximide, a protein synthesis inhibitor, but was completely inhibited by the secretion inhibitor bre feldin A, indicating a posttranslational effect. Treatment of mice wit h TNF-alpha also caused a similar increase in plasma leptin levels. Fi nally, in obese TNF-alpha-deficient mice, circulating leptin levels we re significantly lower, whereas adipose tissue leptin was higher compa red with obese wild-type animals. These data provide evidence that TNF -alpha can act directly on adipocytes to regulate the release of a pre formed pool of leptin, Furthermore, they suggest that the elevated adi pose tissue expression of TNF-alpha that occurs in obesity may contrib ute to obesity-related hyperleptinemia.