Gabriel Tanit L, Tol Marc J, Ottenhof Roelof, van Roomen Cindy, Aten Jan, Claessen Nike, Hooibrink Berend, de Weijer Barbara, Serlie Mireille J, Argmann Carmen, van Elsenburg Leonie, Aerts Johannes M F G, van Eijk Marco
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Diabetes. 2014 Oct;63(10):3310-23. doi: 10.2337/db13-1720. Epub 2014 May 1.
In obesity, adipose tissue (AT) contains crown-like structures where macrophages surround nonviable adipocytes. To understand how AT macrophages (ATMs) contribute to development of insulin resistance, we examined their character in more detail. In silico analysis of F2 mouse populations revealed significant correlation between adipose glycoprotein nonmetastatic melanoma protein B (Gpnmb) expression and body weight. In obese mice and obese individuals, Gpnmb expression was induced in ATMs. Cultured RAW264.7 cells were used to obtain insight into the mechanism of Gpnmb regulation. Gpnmb was potently induced by lysosomal stress inducers, including palmitate and chloroquine, or Torin1, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1). These stimuli also provoked microphthalmia transcription factor (MITF) translocation to the nucleus, and knockdown of MITF by short hairpin RNA indicated its absolute requirement for Gpnmb induction. In agreement with our in vitro data, reduced mTORC1 activity was observed in isolated ATMs from obese mice, which coincided with increased nuclear MITF localization and Gpnmb transcription. Aberrant nutrient sensing provokes lysosomal stress, resulting in attenuated mTORC1 activity and enhanced MITF-dependent Gpnmb induction. Our data identify Gpnmb as a novel marker for obesity-induced ATM infiltration and potentiator of interleukin-4 responses and point toward a crucial role for MITF in driving part of the ATM phenotype.
在肥胖状态下，脂肪组织（AT）中存在冠状结构，其中巨噬细胞围绕着无活力的脂肪细胞。为了了解脂肪组织巨噬细胞（ATM）如何促进胰岛素抵抗的发展，我们更详细地研究了它们的特征。对F2小鼠群体的计算机分析显示，脂肪糖蛋白非转移性黑色素瘤蛋白B（Gpnmb）表达与体重之间存在显著相关性。在肥胖小鼠和肥胖个体中，Gpnmb在ATM中被诱导表达。使用培养的RAW264.7细胞来深入了解Gpnmb的调控机制。Gpnmb可被溶酶体应激诱导剂（包括棕榈酸和氯喹）或雷帕霉素复合物1（mTORC1）的哺乳动物靶点抑制剂Torin1强烈诱导。这些刺激还促使小眼畸形转录因子（MITF）易位至细胞核，短发夹RNA敲低MITF表明其对Gpnmb诱导是绝对必需的。与我们的体外数据一致，在从肥胖小鼠分离的ATM中观察到mTORC1活性降低，这与核MITF定位增加和Gpnmb转录增加相吻合。异常的营养感知引发溶酶体应激，导致mTORC1活性减弱和MITF依赖性Gpnmb诱导增强。我们的数据确定Gpnmb是肥胖诱导的ATM浸润的新型标志物和白细胞介素-4反应的增强剂，并指出MITF在驱动部分ATM表型中起关键作用。
