Diana Le Duc1,2, Chen-Ching Lin3, Yulia Popkova4, Zuqin Yang5, Velluva Akhil6,5, M Volkan Çakir5, Sonja Grunewald7, Jan-Christoph Simon7, Andreas Dietz8, Dirk Dannenberger9, Antje Garten10, Johannes R Lemke11, Jürgen Schiller4, Matthias Blüher12, Pamela Arielle Nono Nankam13, Ulrike Rolle-Kampczyk14, Martin von Bergen14,15, Janet Kelso6, Torsten Schöneberg16. 1. Institute of Human Genetics, University Medical Center Leipzig, 04103, Leipzig, Germany. diana_leduc@eva.mpg.de. 2. Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103, Leipzig, Germany. diana_leduc@eva.mpg.de. 3. Institute of Biomedical Informatics, National Yang-Ming University, Taipei, 11221, Taiwan. 4. Institute for Medical Physics and Biophysics, Medical Faculty, Leipzig University, 04107, Leipzig, Germany. 5. Division of Molecular Biochemistry, Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103, Leipzig, Germany. 6. Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103, Leipzig, Germany. 7. Department of Dermatology, Venereology and Allergology, University Medical Center Leipzig, 04103, Leipzig, Germany. 8. Clinic for Otorhinolaryngology, Head and Neck Surgery, University Medical Center Leipzig, 04103, Leipzig, Germany. 9. Leibniz Institute for Farm Animal Biology, Institute of Muscle Biology and Growth, Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany. 10. Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig University, 04103, Leipzig, Germany. 11. Institute of Human Genetics, University Medical Center Leipzig, 04103, Leipzig, Germany. 12. Helmholtz Institute for Metabolic Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany. 13. Department of Endocrinology, Faculty of Medicine, University of Leipzig, 04103, Leipzig, Germany. 14. Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research GmbH, 04318, Leipzig, Germany. 15. Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Bruederstr. 32, 04103, Leipzig, Germany. 16. Division of Molecular Biochemistry, Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103, Leipzig, Germany. schoberg@medizin.uni-leipzig.de.
Abstract
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.
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.
Authors: Erind Gjermeni; Anna S Kirstein; Florentien Kolbig; Michael Kirchhof; Linnaeus Bundalian; Julius L Katzmann; Ulrich Laufs; Matthias Blüher; Antje Garten; Diana Le Duc Journal: Biomolecules Date: 2021-09-29
Authors: Marek B Körner; Akhil Velluva; Linnaeus Bundalian; Maximilian Radtke; Chen-Ching Lin; Pia Zacher; Tobias Bartolomaeus; Anna S Kirstein; Achmed Mrestani; Nicole Scholz; Konrad Platzer; Anne-Christin Teichmann; Julia Hentschel; Tobias Langenhan; Johannes R Lemke; Antje Garten; Rami Abou Jamra; Diana Le Duc Journal: Sci Rep Date: 2022-08-05 Impact factor: 4.996
Authors: Lisa A G Barth; Michèle Nebe; Hermann Kalwa; Akhil Velluva; Stephanie Kehr; Florentien Kolbig; Patricia Prabutzki; Wieland Kiess; Diana Le Duc; Antje Garten; Anna S Kirstein Journal: Int J Mol Sci Date: 2022-08-29 Impact factor: 6.208