Phenotypic abnormalities in macrophages from leptin-deficient, obese mice
Phenotypic abnormalities in macrophages from leptin-deficient, obese mice
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DOI：
10.1152/ajpcell.1999.276.2.c386
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发表时间：
1999-02-01
影响因子：
5.5
通讯作者：
Diehl, AM
中科院分区：
文献类型：
--
作者：
Lee, FYJ;Li, YB;Diehl, AM
肥胖是一种复杂的综合症，涉及调节食欲和能量稳态的许多不同因素的信号缺陷。外源性瘦素治疗可逆转 ob/ob 小鼠的食欲过盛和肥胖症，该小鼠具有导致瘦素缺乏的突变，证明了该因子及其受体在肥胖综合征中的重要性。具有瘦素受体的细胞已在大脑食欲调节中心之外被发现。因此瘦素具有外周靶点。由于巨噬细胞表达具有信号传导能力的瘦素受体，因此这些细胞在慢性瘦素缺乏期间可能会发生改变。与这一概念一致，本研究鉴定了 ob/ob 小鼠巨噬细胞的几种表型异常，包括解偶联蛋白 2 mRNA 稳态水平降低、线粒体超氧化物和过氧化氢产生增加、CCAAT 增强子结合蛋白 (C/EBP)-β（一种氧化剂敏感转录因子）的组成型激活、白细胞介素 6 和环氧合酶 (COX)-2（两种 C/EBP-β 靶基因）表达增加、并增加 COX-2 依赖性的 PGE(2) 产量。鉴于巨噬细胞在炎症和免疫的一般调节中的重要性，巨噬细胞功能的这些改变可能有助于肥胖相关的病理生理学。
Obesity is a complex syndrome that involves defective signaling by a number of different factors that regulate appetite and energy homeostasis. Treatment with exogenous leptin reverses hyperphagia and obesity in ob/ob mice, which have a mutation that causes leptin deficiency, proving the importance of this factor and its receptors in the obesity syndrome. Cells with leptin receptors have been identified outside of the appetite regulatory centers in the brain. Thus leptin has peripheral targets. Because macrophages express signaling-competent leptin receptors, these cells may be altered during chronic leptin deficiency. Consistent with this concept, the present study identifies several phenotypic abnormalities in macrophages from ob/ob mice, including decreased steady-state levels of uncoupling protein-2 mRNA, increased mitochondrial production of superoxide and hydrogen peroxide, constitutive activation of CCAAT enhancer binding protein (C/EBP)-beta, an oxidant-sensitive transcription factor, increased expression of interleukin-6 and cyclooxygenase (COX)-2, two C/EBP-beta target genes, and increased COX-2-dependent production of PGE(2). Given the importance of macrophages in the general regulation of inflammation and immunity, these alterations in macrophage function may contribute to obesity-related pathophysiology.