Lipocalin 2 in inflammation and metabolic control

描述（由申请人提供）：脂肪组织在代谢适应过程中经历重塑，这对于维持代谢稳态至关重要。这一过程的失调与肥胖症中的脂肪组织功能障碍、炎症和胰岛素抵抗有关。棕色脂肪组织（BAT）的代谢活化和棕色脂肪细胞在白色脂肪组织（WAT）中的募集是某些生理条件下（如冷应激和肾上腺素能刺激）重构过程的重要组成部分。BAT在成年人中的激活和WAT布朗宁最近因其在对抗肥胖中的作用而获得了极大的关注。然而，我们还远未完全了解这种重塑过程是如何调节的，以及涉及哪些因素。我们的实验室一直在研究脂质运载蛋白2（Lcn2）的代谢功能，Lcn2是一种新发现的脂肪因子，在WAT中优先丰富。我们已经发现Lcn2是适应性产热的关键调节剂，在胰岛素抵抗、血脂异常和脂肪肝疾病中起重要作用。在高脂饮食诱导的肥胖过程中，Lcn 2缺乏导致冷暴露引起的BAT产热激活显著受损，BAT活性降低，WAT布朗宁。此外，我们已经确定，Lcn2，作为一个潜在的循环维甲酸（RA）结合蛋白，是必不可少的RA行动在脂肪组织。我们推测Lcn 2通过涉及BAT激活和WAT布朗宁的外周途径在调节能量消耗中起关键作用。WAT是循环Lcn2调节RA对BAT和WAT产热活性的作用的主要来源。提出了四个具体目标来检验这一假设。目的1在小鼠和细胞模型中确定Lcn2在类维生素A代谢和循环RA向脂肪组织的递送和摄取中的作用。目的2建立Stra1（由视黄酸基因1刺激）作为Lcn 2的细胞表面受体在使用功能获得和丧失方法介导脂肪细胞中的细胞RA摄取中的作用。目的3评估代谢适应过程中脂肪来源的Lcn2对BAT产热激活的贡献。目的4评估脂肪来源的Lcn 2对代谢适应期间WATS的布朗宁和能量消耗的贡献。本研究将鉴定并确定Lcn2作为一种新型的循环RA结合蛋白，其控制RA的递送和摄取，从而控制RA对BAT和WAT产热活化和能量消耗的作用。

DESCRIPTION (provided by applicant): Adipose tissue undergoes remodelling during metabolic adaptations, which is essential for maintaining metabolic homeostasis. The dysregulation of this process has been associated with adipose tissue dysfunction, inflammation, and insulin resistance in obesity. The metabolic activation of brown adipose tissue (BAT) and the recruitment of brown adipocytes in white adipose tissue (WAT) are the important components of the remodelling process under certain physiological conditions such as cold stress and adrenergic stimulation. BAT activation in adult humans and WAT browning has recently gained great recognitions for their role in combating obesity. However, we are far from a full understanding of how this remodelling process is regulated and what factors are involved. Our lab has been characterizing metabolic functions of lipocalin 2 (Lcn2), a newly identified adipokine preferentially abundant in WAT. We have discovered that Lcn2 is a critical regulator of adaptive thermogenesis playing an important role in insulin resistance, dyslipidemia, and fatty liver disease. Lcn2 deficiency led to markedly impaired BAT thermogenic activation by cold exposure and reduced BAT activity and browning of WAT during high fat diet-induced obesity. In addition, we have identified that Lcn2, as a potential circulating retinoid acid (RA) biding protein, is essential for RA action in adipose tissue. We hypothesize that Lcn2 plays a key role in regulating energy expenditure via a peripheral pathway involving BAT activation and WAT browning. WAT is the major source of circulating Lcn2 modulating RA action on thermogenic activity in BAT and WAT. Four specific aims are proposed to test the hypothesis. Aim 1 determines the role of Lcn2 in retinoid metabolism and the delivery and uptake of circulating RA to adipose tissue in mouse and cell models. Aim 2 establishes the role of Stra1 (stimulated by retinoic acid gene 1) as a cell surface receptor for Lcn2 in mediating cellular RA uptake in adipocytes using gain- and loss-of-function approaches. Aim 3 assesses the contribution of adipose-derived Lcn2 to BAT thermogenic activation during metabolic adaptations. Aim 4 assesses the contribution of adipose-derived Lcn2 to the browning of WATs and energy expenditure during metabolic adaptations. This study will identify and establish Lcn2 as a novel circulating RA binding protein that controls RA delivery and uptake, thereby action of RA on BAT and WAT thermogenic activation and energy expenditure.