Transmembrane TNF-alpha (tmTNF-alpha) acts both as a ligand, delivering 'forward signaling' via TNFR, and as a receptor, transducing 'reverse signaling'. The contradiction of available data regarding the effect of tmTNF-alpha on insulin resistance may be due to imbalance in both signals. Here, we demonstrated that high glucose-induced impairment of insulin-stimulated glucose uptake by 3T3-L1 adipocytes was concomitant with decreased tmTNF-alpha expression and increased soluble TNF-alpha (sTNF-alpha) secretion. However, when TACE was inhibited, preventing the conversion of tmTNF-alpha to sTNF-alpha, this insulin resistance was partially reversed, indicating a salutary role of tmTNF-alpha. Treatment of 3T3-L1 adipocytes with exogenous tmTNF-alpha promoted insulin-induced phosphorylation of IRS-1 and Akt, facilitated GLUT4 expression and membrane translocation, and increased glucose uptake while addition of sTNF-alpha resulted in the opposite effect. Furthermore, tmTNF-alpha downregulated the production of IL-6 and MCP-1 via NF-kappa B inactivation, as silencing of A20, an inhibitor for NF-kappa B, by siRNA, abolished this effect of tmTNF-alpha. However, tmTNF-alpha upregulated adiponectin expression through the PPAR-gamma pathway, as inhibition of PPAR-gamma by GW9662 abrogated both tmTNF-alpha-induced adiponectin transcription and glucose uptake. Our data suggest that tmTNF-alpha functions as an insulin sensitizer via forward signaling. (C) 2015 Elsevier Ireland Ltd. All rights reserved.