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

TNF-α 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-α requires the synthesis of NO. TNF-α 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-α stimulates NOS catalytic activity. Pre-treatment with TNF-α 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.