Institute of Human Genetics, University Medical Center Leipzig, 04103, Leipzig, Germany.
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103, Leipzig, Germany.
Int J Obes (Lond). 2021 Mar;45(3):565-576. doi: 10.1038/s41366-020-00716-y. Epub 2020 Nov 24.
Elucidation of lipid metabolism and accumulation mechanisms is of paramount importance to understanding obesity and unveiling therapeutic targets. In vitro cell models have been extensively used for these purposes, yet, they do not entirely reflect the in vivo setup. Conventional lipomas, characterized by the presence of mature adipocytes and increased adipogenesis, could overcome the drawbacks of cell cultures. Also, they have the unique advantage of easily accessible matched controls in the form of subcutaneous adipose tissue (SAT) from the same individual. We aimed to determine whether lipomas are a good model to understand lipid accumulation.
We histologically compared lipomas and control SAT, followed by assessment of the lipidome using high-resolution H NMR spectroscopy and ESI-IT mass spectrometry. RNA-sequencing was used to obtain the transcriptome of lipomas and the matched SAT.
We found a significant increase of small-size (maximal axis < 70 µm) and very big (maximal axis > 150 µm) adipocytes within lipomas. This suggests both enhanced adipocyte proliferation and increased lipid accumulation. We further show that there is no significant change in the lipid composition compared to matched SAT. To better delineate the pathophysiology of lipid accumulation, we considered two groups with different genetic backgrounds: (1) lipomas with HMGA2 fusions and (2) without gene fusions. To reduce the search space for genes that are relevant for lipid pathophysiology, we focused on the overlapping differentially expressed (DE) genes between the two groups. Gene Ontology analysis revealed that DE genes are enriched in pathways related to lipid accumulation.
We show that the common shared lipid accumulation mechanism in lipoma is a reduction in lipolysis, with most gene dysregulations leading to a reduced cAMP in the adipocyte. Superficial lipomas could thus be used as a model for lipid accumulation through altered lipolysis as found in obese patients.
阐明脂质代谢和积累机制对于理解肥胖症和揭示治疗靶点至关重要。体外细胞模型已被广泛用于这些目的，但它们并不能完全反映体内的情况。传统的脂肪瘤，其特征是存在成熟的脂肪细胞和增加的脂肪生成，可以克服细胞培养的缺点。此外，它们还有一个独特的优势，即可以从同一个体中获得容易获得的匹配对照物，即皮下脂肪组织（SAT）。我们旨在确定脂肪瘤是否是理解脂质积累的良好模型。
我们对脂肪瘤和对照 SAT 进行了组织学比较，然后使用高分辨率 H NMR 光谱和 ESI-IT 质谱法评估脂质组。RNA 测序用于获得脂肪瘤和匹配 SAT 的转录组。
我们发现脂肪瘤内存在大量小尺寸（最大轴<70μm）和非常大尺寸（最大轴>150μm）的脂肪细胞显著增加。这表明脂肪细胞增殖增强和脂质积累增加。我们还表明，与匹配 SAT 相比，脂质组成没有显著变化。为了更好地描绘脂质积累的病理生理学，我们考虑了两种具有不同遗传背景的组：（1）具有 HMGA2 融合的脂肪瘤和（2）没有基因融合的脂肪瘤。为了减少与脂质病理生理学相关的基因的搜索空间，我们专注于两组之间重叠的差异表达（DE）基因。GO 分析表明，DE 基因富集在与脂质积累相关的途径中。
我们表明，脂肪瘤中常见的共同脂质积累机制是脂解作用减少，大多数基因失调导致脂肪细胞中的 cAMP 减少。因此，浅层脂肪瘤可以通过肥胖患者中发现的改变的脂解作用作为脂质积累的模型。
