Anti-inflammatory agents inhibit the induction of leptin by tumor necrosis factor-alpha.

Abstract

Tumor necrosis factor (TNF)-alpha stimulates the secretion of the adipocyte-derived hormone leptin. However, the cellular mechanisms by which TNF-alpha influences leptin production are poorly understood. To examine this issue, epididymal fat pads were isolated from mice and cultured in recombinant murine TNF-alpha (100 ng/ml). Compared with medium-treated controls, steady-state leptin expression was increased in TNF-alpha-treated explants. Culture with inhibitors of translation (cycloheximide) or transcription (actinomycin-D) abrogated the induction of leptin following TNF-alpha. Explants were also cultured in the presence of the anti-inflammatory p38 mitogen-activated protein kinase inhibitor (SB-203580) or PG J(2) metabolite [15-deoxy-Delta(12,14)-PG J(2) (PGJ)] and then exposed to TNF-alpha. Both compounds completely abolished TNF-alpha-induced increases in leptin production. To test the relevance of this in vivo, mice were pretreated with PGJ and then given TNF-alpha. PGJ treatment markedly blunted the TNF-alpha-induced increase in leptin, TNF-alpha, and interleukin-6 gene expression in epididymal adipose tissue. Collectively, these data indicate that TNF-alpha acutely activates leptin expression and that anti-inflammatory agents can abrogate TNF-alpha-induced hyperleptinemia.