Lipocalin 2 in inflammation and metabolic control

描述(申请人提供)：脂肪组织在新陈代谢适应过程中经历重塑，这对维持新陈代谢平衡至关重要。这一过程的失调与肥胖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)的代谢激活和白色脂肪组织(WAT)中棕色脂肪细胞的募集是冷应激和肾上腺素能刺激等生理条件下重建过程的重要组成部分。最近，成年人和Wat Browning的蝙蝠激活在对抗肥胖方面的作用得到了极大的认可。然而，我们远未完全了解这一重塑过程是如何监管的，涉及哪些因素。我们的实验室一直在研究Lipocalin 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。我们发现Lcn2是适应性产热的关键调节因子，在胰岛素抵抗、血脂异常和脂肪肝疾病中发挥重要作用。在高脂饮食诱导的肥胖过程中，Lcn2缺乏导致BAT冷暴露的产热激活明显减弱，并降低了BAT的活性和WAT的褐变。此外，我们还发现Lcn2是一种潜在的循环维甲酸(RA)结合蛋白，在脂肪组织中对RA的作用是必不可少的。我们推测，Lcn2通过BAT激活和Wat褐变的外周途径在调节能量消耗中发挥关键作用。Wat是循环Lcn2调节RA对BAT和WAT生热活性作用的主要来源。为了检验这一假说，本文提出了四个具体目标。目的1在小鼠和细胞模型中确定Lcn2在维甲酸代谢和循环维甲酸向脂肪组织的转运和摄取中的作用。目的2通过获得和丧失功能的方法，确定Stra1(由维甲酸基因1刺激)作为Lcn2的细胞表面受体在介导脂肪细胞对RA摄取中的作用。目的3评估脂肪来源的Lcn2在代谢适应过程中对BAT产热激活的贡献。目的4评估脂肪来源的Lcn2在代谢适应过程中对水的褐变和能量消耗的贡献。本研究将发现并确定Lcn2是一种新的循环RA结合蛋白，它控制RA的转运和摄取，从而作用于BAT和WAT的生热激活和能量消耗。

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.