Reduced lipolysis in lipoma phenocopies lipid accumulation in obesity.

BACKGROUND: 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. METHODS: We 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. RESULTS: 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. CONCLUSIONS: 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.

Dicer-processed small RNAs: rules and exceptions.

Canonical microRNAs are excised from their hairpin-shaped precursors by Dicer. In order to find possible exceptions to this rule and to identify additional substrates for Dicer processing we re-evaluate the small RNA sequencing data of the Dicer knockdown experiment in MCF-7 cells orignally published by Friedländer et al. [Friedländer et al., 2012, Nucleic Acids Res 40:37-52]. While the well-known non-Dicer mir-451 is not sufficiently expressed in these experiments, there are several additional Dicer-independent microRNAs, among them the important tumor supressor mir-663a. We recover previously described examples of non-miRNA Dicer substrates such as tRNA-Gln and several snoRNAs. Interestingly, sdRNAs derived from box C/D snoRNAs are Dicer-independent, while those derived from box H/ACA snoRNAs are often Dicer dependent. Several pol-III transcripts, in particular the vault RNAs and the great ape specific snaRs are processed by Dicer, while the small RNAs originating from Y RNAs seem to be Dicer independent.