Studies on the Development and Consequences of Neuroinflammation in Obesity

Abstract

In the past decade, evidence has emerged that obesity induces a neuroinflammatory response in the hypothalamus, a part of the brain that contains neuronal circuitry controlling feeding and metabolism. The potential contribution of non-neuronal central nervous system (CNS) cells, including glia, to the regulation of energy homeostasis has only recently begun to be appreciated. Here we report on the role of two glial cell types, astrocytes and microglia, which act in concert as mediators of the neuroinflammatory response of the CNS. Neuroinflammation is thought to take place in two phases: an early “acute” phase necessary for homeostatic and defense mechanisms and a self-perpetuating long-term “chronic” phase associated with neurologic disease. The results herein describe evidence for opposing roles of this biphasic pattern of neuroinflammation in the regulation of energy homeostasis and the pathophysiology of obesity. Using mice with green-fluorescent protein (GFP)-labeled immune cells in peripheral circulation, we show that chronic high-fat diet (HFD) intake increases recruitment of monocytes in to the brain. Histological examination showed that these cells acquire morphology similar to activated phagocytic microglia, suggesting that recruitment of peripheral immune cells into the CNS may contribute to the neuroinflammatory response to obesity. Further studies were then conducted to describe the localization and activation of astrocytes in obesity. Increased expression of the astrocyte activation marker GFAP was found within several nuclei of the hypothalamus following chronic exposure to HFD. We also found that astrocytes in the hypothalamus were activated acutely after high-fat feeding. To begin to address the physiological significance of astrocyte activation to the regulation of energy homeostasis we examined the effect of inactivation of astroglial NF-κB, an essential component of astrocyte activation, on food intake. Suppression of NF-κB signaling in astrocytes in a tetracycline-inducible transgenic mouse model led to increased food intake following acute exposure to a HFD. This study provides novel evidence that astrocytes have a regulatory role in the regulation of feeding behavior in response to HFD.