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

肥胖及其相关的共病，如动脉硬化、2型糖尿病和高血压，已成为工业化富裕社会的最大健康风险之一。富含不饱和脂肪酸的高脂肪饮食(HFD)的消费增加是这种不利发展的主要罪魁祸首。下丘脑是大脑中的一个小区域。下丘脑通过其神经回路和神经肽，通过维持食物摄入量和能量消耗之间的平衡，成为体重的主要调节器。在肥胖人群中，下丘脑对能量平衡的调节受到损害。尽管目前的研究已经提供了关于下丘脑神经网络功能的全面数据，但肥胖症中神经元变化的机制尚未完全了解。肥胖者脂肪组织和肝脏中的炎症已被频繁报道。然而，在最近几年，实验可以为早在肥胖开始之前就喂食高脂饮食的啮齿动物的下丘脑的炎症过程提供证据。星形胶质细胞和小胶质细胞的激活已被证明是启动下丘脑炎症的一个特征。据推测，长期食用HFD会导致持续的胶质细胞激活和慢性炎症。这会引发能量平衡受损和下丘脑炎症的恶性循环，最终导致进行性体重增加和肥胖。然而，关于HFD衍生的代谢因子(如饱和脂肪酸)如何引发下丘脑炎症反应的分子机制还知之甚少。我们最近证明，神经节苷脂是一类在大脑中高度丰富的糖基化神经鞘糖脂，是下丘脑神经元受体信号的重要调节因子，对于适当调节能量平衡和体重控制至关重要。本研究旨在揭示神经节苷脂在下丘脑星形胶质细胞中的功能。因此，我们将研究星形胶质细胞特异性抑制小鼠神经节苷脂生物合成是否可以改变HFD诱导的星形胶质细胞激活以及随后的下丘脑炎症和肥胖。此外，还应研究神经节苷脂与Toll样受体(TLR)-4的相互作用。TLR4已被证明在HFD诱导的星形胶质细胞激活中起主要作用，但神经节苷脂对下丘脑星形胶质细胞TLR4信号的调节从未被研究过。因此，我们将研究神经节苷脂缺乏的原代培养的星形胶质细胞暴露在饱和脂肪酸中的TLR4信号。综上所述，这些发现有望进一步阐明神经节苷脂在HFD诱导的星形胶质细胞激活过程中的作用以及随之而来的下丘脑炎症。这项研究可能强调星形细胞神经节苷脂作为治疗下丘脑炎症性肥胖的新的潜在靶点。

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.