Central administration of interleukin-4 exacerbates hypothalamic inflammation and weight gain during high-fat feeding

Oh-I S, Thaler JP, Ogimoto K, Wisse BE, Morton GJ, Schwartz MW. Central administration of interleukin-4 exacerbates hypothalamic inflammation and weight gain during high-fat feeding. Am J Physiol Endocrinol Metab 299: E47-E53, 2010. First published April 6, 2010; doi:10.1152/ajpendo.00026.2010.-Inperipheral tissues, the link between obesity and insulin resistance involves low-grade inflammation induced by macrophage activation and proinflammatory cytokine signaling. Since proinflammatory cytokines are also induced in the hypothalamus of animals placed on a high-fat (HF) diet and can inhibit neuronal signal transduction pathways required for normal energy homeostasis, hypothalamic inflammation is hypothesized to contribute to the pathogenesis of diet-induced obesity (DIO). We addressed this hypothesis by perturbing the inflammatory milieu of the hypothalamus in adult male Wistar rats using intracerebroventricular (icv) administration of interleukin-4 (IL-4), a Th2 cytokine that promotes alternative activation (M2) of macrophages and microglia. During HF feeding, icv IL-4 administration increased hypothalamic proinflammatory cytokine gene expression and caused excess weight gain. Intracerebroventricular pretreatment with PS1145, an inhibitor of IKK beta (a key intracellular mediator of inflammatory signaling), blocked both IL-4 effects, suggesting a causal relationship between IL-4-induced weight gain and hypothalamic inflammation. These observations add to growing evidence linking hypothalamic inflammation to obesity pathogenesis.