Nisoli Enzo, Regianini Laura, Briscini Luca, Bulbarelli Alessandra, Busetto Luca, Coin Alessandra, Enzi Giuliano, Carruba Michele O
Center for Study and Research on Obesity, Department of Preclinical Sciences, LITA Vialba, L. Sacco Hospital, University of Milan, Via G. B. Grassi 74, Italy.
J Pathol. 2002 Nov;198(3):378-87. doi: 10.1002/path.1212.
Multiple symmetric lipomatosis (MSL) is an inherited disorder in which enlarging and unencapsulated lipomas symmetrically develop in the subcutaneous tissue of the neck, shoulders, mammary, and truncal regions. In some cases, it is associated with mitochondrial DNA abnormalities. The pathogenesis of MSL is completely unknown, although the fat deposits may be due to a neoplastic-like proliferation of functionally defective brown adipocytes. It has recently been demonstrated that the beta(3)-adrenergic receptor is the functionally relevant adrenergic receptor subtype in brown adipocytes and that its stimulation by noradrenaline (NA) modulates the expression of genes, such as uncoupling protein (UCP)-1 and inducible nitric oxide synthase (iNOS), involved in fat cell proliferation and differentiation. Furthermore, Trp64Arg mutation of the beta(3)-adrenoceptor has been implicated in lower NA activity in adipose tissues. The aim of this study was to investigate the molecular and functional characteristics of MSL adipocytes and to analyse the effects of nitric oxide (NO) on the proliferation/differentiation of MSL adipocytes in culture, and the relevance of putative noradrenergic deficit in the development of lipomas in MSL patients. Cultured MSL adipocytes were able to synthesize UCP-1 (the selective marker of brown adipocytes), but unlike that of normally functioning brown fat cells, the expression of the UCP-1 gene was not significantly induced by NA. NA is also defective in inducing iNOS gene expression, thus leading to reduced NO production and a consequent reduction in the anti-proliferative, adipogenic (mitochondrial biogenesis) effects of NA on MSL cells. Furthermore, the transcriptional peroxisome proliferator-activated receptor gamma co-activator-1 (PGC-1), which plays a key role in the sympathetic-stimulated mitochondrial biogenesis of brown adipocytes, is expressed but not induced by NA in MSL cells, as it is in brown adipocytes. The study did not find any association between beta(3)-adrenoceptor gene polymorphism and noradrenergic signalling defects in MSL subjects with or without mitochondrial DNA mutations.
多发性对称性脂肪瘤病（MSL）是一种遗传性疾病，在颈部、肩部、乳腺和躯干区域的皮下组织中，会对称地出现不断增大且无包膜的脂肪瘤。在某些情况下，它与线粒体DNA异常有关。尽管脂肪沉积可能是由于功能缺陷的褐色脂肪细胞发生肿瘤样增殖所致，但MSL的发病机制完全未知。最近有研究表明，β(3)-肾上腺素能受体是褐色脂肪细胞中功能相关的肾上腺素能受体亚型，去甲肾上腺素（NA）对其刺激可调节参与脂肪细胞增殖和分化的基因表达，如解偶联蛋白（UCP）-1和诱导型一氧化氮合酶（iNOS）。此外，β(3)-肾上腺素能受体的Trp64Arg突变与脂肪组织中NA活性降低有关。本研究的目的是调查MSL脂肪细胞的分子和功能特征，分析一氧化氮（NO）对培养的MSL脂肪细胞增殖/分化的影响，以及推测的去甲肾上腺素能缺陷在MSL患者脂肪瘤形成中的相关性。培养的MSL脂肪细胞能够合成UCP-1（褐色脂肪细胞的选择性标志物），但与正常功能的褐色脂肪细胞不同，UCP-1基因的表达不会被NA显著诱导。NA在诱导iNOS基因表达方面也存在缺陷，从而导致NO生成减少，进而使NA对MSL细胞的抗增殖、成脂（线粒体生物发生）作用降低。此外，在褐色脂肪细胞中，转录过氧化物酶体增殖物激活受体γ共激活因子-1（PGC-1）在交感神经刺激的褐色脂肪细胞线粒体生物发生中起关键作用，在MSL细胞中也有表达，但不会被NA诱导，与褐色脂肪细胞情况相同。该研究未发现β(3)-肾上腺素能受体基因多态性与有无线粒体DNA突变的MSL受试者的去甲肾上腺素能信号缺陷之间存在任何关联。
