Reduced lipolysis in lipoma phenocopies lipid accumulation in obesity

Diana Le Duc,Pamela Arielle Nono Nankam,Johannes R Lemke,Velluva Akhil,Matthias Blüher,Ulrike Rolle-Kampczyk,Torsten Schöneberg,Andreas Dietz,Zuqin Yang,Jan-Christoph Simon,Yulia Popkova,Martin Von Bergen,Dirk Dannenberger,Sonja Grunewald,Chen-Ching Lin,Jürgen Schiller,M Volkan Çakir,Antje Garten,Janet Kelso

doi:10.1038/s41366-020-00716-y

Abstract

BackgroundElucidation 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.MethodsWe histologically compared lipomas and control SAT, followed by assessment of the lipidome using high-resolution 1H NMR spectroscopy and ESI-IT mass spectrometry. RNA-sequencing was used to obtain the transcriptome of lipomas and the matched SAT.ResultsWe 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.ConclusionsWe 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.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Extended author information available on the last page of the articleObesity is one of the most significant health burdens worldwide
The major drawback here is that it is impossible to control for donor-related factors or environmental exposure, which would facilitate a better understanding of adipogenesis and lipid accumulation triggers
Based on gene expression profiles, we show that the overlap of differentially expressed (DE) genes between lipomas with HMGA2 fusions and without any fusion genes is significant, supporting our initial hypothesis

Summary

Introduction

An in vitro setup allows using human material, which facilitates the applicability of the results toward the human disease While these models enable a controlled investigation of adipogenesis regulators, they do not entirely reflect in vivo adipogenesis, since the in vitro setup requires a series of defined adipogenic cocktails for differentiation or fat accumulation [3]. Conventional lipomas, characterized by the presence of mature adipocytes and increased adipogenesis, could overcome the drawbacks of cell cultures. They have the unique advantage of 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

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Conclusion