The nuclear receptor PPAR gamma is a lipid sensor that regulates lipid metabolism through gene transcription. Inhibition of PPAR gamma activity by TNF-alpha is involved in pathogenesis of insulin resistance, atherosclerosis, inflammation, and cancer cachexia. PPAR gamma activity is regulated by TNF-alpha at pre-translational and post-translational levels. Activation of serine kinases including IKK, ERK, JNK, and p38 may be involved in the TNF-regulation of PPAR gamma. Of the four kinases, IKK is a dominant signaling molecule in the TNF-regulation of PPAR gamma. IKK acts through at least two mechanisms: inhibition of PPAR gamma expression and activation of PPAR gamma corepressor. In this review article, literature is reviewed with a focus on the mechanisms of PPAR gamma inhibition by TNF-alpha. (C) 2008 Elsevier Inc. All rights reserved.