Hypothalamic Inflammation and Energy Homeostasis

下丘脑炎症和能量稳态

• 批准号: 8021873
• 负责人: Michael W Schwartz
• 金额: $ 41.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8021873
• 关键词: Hypothalamic; Inflammation; Energy; Homeostasis

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.

描述（由申请人提供）：外周组织中的炎症是胰岛素抵抗和肥胖的其他代谢后果的关键介导物。最近的研究表明，类似的炎症过程也发生在下丘脑中，并且与外周组织中的炎症不同，该过程是肥胖和相关代谢障碍的潜在原因（而不仅仅是后果）。下丘脑炎症的这些作用部分通过受损的神经元对激素胰岛素和瘦素的反应介导，胰岛素和瘦素是能量稳态和胰岛素敏感性的中枢控制的关键信号。我们的新发现，下丘脑促炎细胞因子的表达发生在高脂（HF）喂养开始后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和对HF饮食的摄食反应之间存在联系。与这些早期反应相一致的是，小胶质细胞（大脑的巨噬细胞）聚集在弓状核（ARC，一个关键的下丘脑区域，用于感知来自胰岛素和瘦素的输入），而不是其他大脑区域。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由3周HF喂养诱导的全身胰岛素抵抗。在这里，我们提出的研究，以确定下丘脑小胶质细胞和神经元对HF喂养的反应的时间过程，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中小胶质细胞积聚的潜在机制，并确定这种小胶质细胞反应的中断是否易患肥胖症。最后，我们将探讨HF喂养诱导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喂养诱导的体重增加和代谢障碍，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。 公共卫生关系：该提案的重点是高脂肪喂养导致肥胖和胰岛素抵抗的机制，这两个问题都是全球主要的公共卫生问题。越来越多的证据表明，外周组织炎症是胰岛素抵抗和肥胖的其他代谢后果的主要原因。在高脂肪喂养过程中，下丘脑也会发生炎症，下丘脑是控制体重和葡萄糖代谢的关键大脑区域。与外周组织的炎症不同，下丘脑炎症是肥胖和胰岛素抵抗的原因（而不仅仅是结果）。通过阐明下丘脑炎症这些影响的机制，我们的研究将促进我们对肥胖发病机制及其与代谢功能障碍的联系的了解，并确定治疗这些疾病的新潜在靶点。