Inducible-NOS but not neuronal-NOS participate in the acute effect of TNF-α on hypothalamic insulin-dependent inhibition of food intake

TNF-alpha acts on the hypothalamus modulating food intake and energy expenditure through mechanisms incompletely elucidated. Here, we explore the hypothesis that, to modulate insulin-induced anorexigenic signaling in hypothalamus, TNF-a requires the synthesis of NO. TNF-alpha activates signal transduction through JNK and p38 in hypothalamus, peaking at 10(-8) M. This is accompanied by the induction of expression of the inducible and neuronal forms of NOS, in both cases peaking at 10(-12) M. In addition, TNF-alpha stimulates NOS catalytic activity. Pre-treatment with TNF-alpha at a low dose (10(-12) M) inhibits insulin-dependent anorexigenic signaling, and this effect is abolished in iNOS but not in nNOS knockout mice. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.