TNF-alpha TRANSIENTLY INDUCES ENDOPLASMIC RETICULUM STRESS AND AN INCOMPLETE UNFOLDED PROTEIN RESPONSE IN THE HYPOTHALAMUS

Abstract

In diet-induced obesity, hypothalamic inflammation is triggered as an outcome of prolonged exposure to dietary fats. Toll-like receptor 4 (TLR4) activation plays a central role in this process, inducing endoplasmic reticulum stress and activating inflammatory cytokine gene transcription. Although saturated fatty acids can induce endoplasmic reticulum stress in the hypothalamus, it is unknown whether inflammatory cytokines alone can activate this mechanism. Here, rats were treated with TNF-alpha or lyposaccharide (LPS) and endoplasmic reticulum stress and unfolded protein response were evaluated by immunoblot and polymerase chain reaction (PCR). Activation of TLR4 by LPS was capable of inducing a complete endoplasmic reticulum stress and unfolded protein response through the PERK/eIF2 alpha and IRE1 alpha/XBP1 pathways. Conversely, TNF-a, injected either locally or systemically, was unable to induce a complete program of unfolded protein response, although the activation of endoplasmic reticulum stress was achieved to a certain degree. Thus, in the hypothalamus, the isolated action of TNF-alpha is insufficient to produce the activation of a complete program of unfolded protein response. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: obesity, diabetes, food intake, leptin, insulin, cytokine.