The role of astrocytic gangliosides in high-fat-diet-induced hypothalamic inflammation

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Obesity and its associated co-morbidities, such as arteriosclerosis, type 2 diabetes and hypertension, has become one of the biggest health risks of industrialized affluent societies. An increase in the consumption of high-fat diets (HFD) rich in unsaturated fatty acids is a major culprit in this unfavorable development. The hypothalamus is a small region in the the brain. With its neuronal circuits and neuropeptides, the hypothalamus is the main regulator of body weight, by maintaining the balance between food intake and energy expenditure. In obese individuals, hypothalamic regulation of energy balance is impaired. Even though current research has provided comprehensive data on the function of hypothalamic neuronal networks, the mechanisms underlying neuronal alterations in obesity are not yet completely understood.Inflammation in adipose tissue and the liver of obese individuals has been reported frequently. However, during the recent years experiments could provide evidence for inflammatory processes in the hypothalamus of HFD-fed rodents long before the onset of obesity. Activation of astrocytes and microglia has been documented as a characteristic feature in the initiation of hypothalamic inflammation. It is assumed that long-term consumption of HFD leads to sustained glial activation and chronic inflammation. This initiates a vicious circle of impaired energy balance and hypothalamic inflammation, eventually perpetuating progressive weight gain and obesity. However, molecular mechanisms as to how HFD-derived metabolic factors such as saturated fatty acids can initiate a hypothalamic inflammatory response are poorly understood. We have recently demonstrated that gangliosides, a specific class of glycosylated sphingolipids highly enriched in the brain, are important regulators of neuronal receptor signaling in the hypothalamus and vital for a proper regulation of energy homeostasis and body weight control. In the present study, we aim to unravel the function of gangliosides in hypothalamic astrocytes. Therefore, we will study whether astrocyte-specific inhibition of ganglioside biosynthesis in mice can alter HFD-induced astrocytic activation and subsequent hypothalamic inflammation and obesity. Additionally, the interaction of gangliosides with the Toll-like receptor (TLR)-4 shall be investigated. TLR4 has been shown to play a major role in HFD-induced astrocytic activation, but the regulation of astrocytic TLR4 signaling by gangliosides in the hypothalamus has never been studied. Therefore, we will investigate the TLR4 signaling in ganglioside-depleted primary astrocyte cultures exposed to saturated fatty acids.Taken together, these findings are expected to shed more light on the role of gangliosides in the HFD-induced activation process of astrocytes and the consequent hypothalamic inflammation. This study might highlight astrocytic gangliosides as a new potential target in the treatment of hypothalamic-inflammation-induced obesity.