Obese adipose tissue is characterized by an excessive production of inflammatory adipokines including tumor necrosis factor-alpha (TNF-alpha) TNF-alpha stimulates free fatty acid (FFA) secretion through adipocyte lipolysis, and increased plasma levels of FFA promote insulin resistance In this report, we show that hesperetin and naringenin, two citrus flavonoids, inhibit TNF-alpha-stimulated FFA secretion from mouse adipocytes These flavonoids block the TNF-alpha-induced activation of the NF-kappa B and ERK pathways Moreover, hesperetin and naringenin prevent TNF-alpha from downregulating the transcription of two antilipolytic genes, perilipin and PDE3B These effects are mediated through the inhibition of the ERK pathway In contrast, the inhibition of the NF-kappa B pathway by hesperetin and naringenin suppresses the transcription of IL-6, which induces FFA secretion in an autocrine manner Our results provide novel evidence that hesperetin and naringenin directly inhibit TNF-alpha-stimulated FFA secretion These findings may be useful for ameliorating FFA-induced insulin resistance (C) 2010 Elsevier Inc All rights reserved