Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids

Choi SJ, Kim F, Schwartz MW, Wisse BE. Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids. Am J Physiol Endocrinol Metab 298: E1122-E1130, 2010. First published March 30, 2010; doi:10.1152/ajpendo.00006.2010.-Hypothalamic inflammation induced by high-fat feeding causes insulin and leptin resistance and contributes to the pathogenesis of obesity. Since in vitro exposure to saturated fatty acids causes inflammation and insulin resistance in many cultured cell types, we determined how cultured hypothalamic neurons respond to this stimulus. Two murine hypothalamic neuronal cell cultures, N43/5 and GT1-7, were exposed to escalating concentrations of saturated fatty acids for up to 24 h. Harvested cells were evaluated for activation of inflammation by gene expression and protein content. Insulin-treated cells were evaluated for induction of markers of insulin receptor signaling (p-IRS, p-Akt). In both hypothalamic cell lines, inflammation was induced by prototypical inflammatory mediators LPS and TNF alpha, as judged by induction of I kappa B alpha (3- to 5-fold) and IL-6 (3- to 7-fold) mRNA and p-I kappa B alpha protein, and TNF alpha pretreatment reduced insulin-mediated p-Akt activation by 30% (P < 0.05). By comparison, neither mixed saturated fatty acid (100, 250, or 500 mu M for <= 6 h) nor palmitate exposure alone (200 mu M for <= 24 h) caused inflammatory activation or insulin resistance in cultured hypothalamic neurons, whereas they did in control muscle and endothelial cell lines. Despite the lack of evidence of inflammatory signaling, saturated fatty acid exposure in cultured hypothalamic neurons causes endoplasmic reticulum stress, induces mitogen-activated protein kinase, and causes apoptotic cell death with prolonged exposure. We conclude that saturated fatty acid exposure does not induce inflammatory signaling or insulin resistance in cultured hypothalamic neurons. Therefore, hypothalamic neuronal inflammation in the setting of DIO may involve an indirect mechanism mediated by saturated fatty acids on nonneuronal cells.