Hypothalamic Inflammation and Energy Homeostasis

描述（由申请人提供）：外周组织炎症被认为是胰岛素抵抗和肥胖其他代谢后果的关键媒介。最近的研究表明，类似的炎症过程也发生在下丘脑，并且与外周组织的炎症不同，这一过程是肥胖和相关代谢障碍的潜在原因（而不仅仅是结果）。下丘脑炎症的这些影响部分是通过神经元对激素胰岛素和瘦素的反应受损介导的，这两种激素是能量稳态和胰岛素敏感性中枢控制的关键信号。我们的新发现是，下丘脑促炎细胞因子的表达发生在高脂肪（HF）喂养开始的24小时内，这种效应与热量摄入的显着增加相一致，并且这两个参数在随后的一周内逐渐恢复正常，这表明神经元炎症反应与高脂肪饮食的贪食反应之间存在联系。与这些早期反应一致的是，小胶质细胞（大脑的巨噬细胞）聚集在弓状核（ARC，下丘脑感知胰岛素和瘦素输入的关键区域），而不是大脑的其他区域。这些和其他观察结果强烈表明，下丘脑神经元和小胶质细胞之间的相互作用是HF喂养期间体重增加的决定因素。此外，下丘脑炎症的急性逆转完全逆转了3周HF喂养引起的全身胰岛素抵抗。在这里，我们建议研究确定下丘脑小胶质细胞和神经元对HF喂养反应的时间过程，以及这种炎症是否需要小胶质细胞、神经元或两种细胞类型的反应。我们还将确定HF喂养期间ARC中小胶质细胞积累的机制，并确定这种小胶质细胞反应的破坏是否容易导致肥胖。最后，我们将探讨HF喂养引起的下丘脑炎症信号导致胰岛素抵抗的机制。这些研究将阐明下丘脑神经元和小胶质细胞之间的相互作用如何影响HF喂养引起的体重增加和代谢损伤，这将使我们了解肥胖和胰岛素抵抗的发病机制，并促进发现治疗和预防这些疾病的新方法。

DESCRIPTION (provided by applicant): Inflammation in peripheral tissues is implicated as a key mediator of insulin resistance and other metabolic consequences of obesity. Recent studies show that a similar inflammatory process also occurs in the hypothalamus, and that this process, unlike inflammation in peripheral tissues, is a potential cause (and not just a consequence) of obesity and associated metabolic impairment. These effects of hypothalamic inflammation are mediated in part via impaired neuronal responses to the hormones insulin and leptin, key signals in the central control of both energy homeostasis and insulin sensitivity. Our novel findings that hypothalamic proinflammatory cytokine expression occurs within just 24 h of the onset of high-fat (HF) feeding, an effect that coincides with a marked increase of caloric intake, and that both parameters are gradually return to normal over the subsequent week suggest a link between neuronal inflammatory responses and the hyperphagic response to a HF diet. Coincident with these early responses, microglia (the macrophage of the brain) accumulate in the arcuate nucleus (ARC, a key hypothalamic area for sensing input from insulin and leptin) - but not other brain areas. These and other observations strongly suggest that interactions between hypothalamic neurons and microglia are determinants of weight gain during HF feeding. Further, acute reversal of hypothalamic inflammation fully reverses systemic insulin resistance induced by 3 wk of HF feeding. Here, we propose studies to determine the time course over which hypothalamic microglia and neurons respond to HF feeding, and whether the response of microglia, neurons, or both cell types is required for this inflammation. We will also identify mechanisms underlying microglial accumulation in the ARC during HF feeding, and determine whether disruption of this microglial response predisposes to obesity. Lastly, we will investigate the mechanism whereby hypothalamic inflammatory signaling induced by HF feeding causes insulin resistance. These studies will clarify how interactions between hypothalamic neurons and microglia influence weight gain and metabolic impairment induced by HF feeding, which will inform our understanding of the pathogenesis of both obesity and insulin resistance and facilitate the discovery of new approaches to the treatment and prevention of these disorders. PUBLIC HEALTH RELEVANCE: This proposal focuses on mechanisms whereby high-fat feeding causes obesity and insulin resistance, both of which are major public health problems worldwide. Growing evidence implicates inflammation in peripheral tissues as a major cause of insulin resistance and other metabolic consequences of obesity. During high-fat feeding, inflammation also occurs in the hypothalamus, a key brain area for the control of both body weight and glucose metabolism. Unlike inflammation in peripheral tissues, hypothalamic inflammation is implicated as a cause (and not just a consequence) of both obesity and insulin resistance. By clarifying the mechanisms underlying these effects of hypothalamic inflammation, our studies will advance our understanding of obesity pathogenesis and its links to metabolic dysfunction, and identify new potential targets for the treatment of these conditions.