Transcriptomics of Subcutaneous Tissue of Lipedema Identified Differentially Expressed Genes Involved in Adipogenesis, Inflammation, and Pain

Abstract

Background: Lipedema is a disease typically affecting women with a symmetrical, painful fat distribution disorder, which is hypothesized to be caused by impaired adipogenesis, inflammation, and extracellular matrix remodeling, leading to fibrosis and the development of edema in lipedema subcutaneous adipose tissue. The pathogenesis and molecular processes leading to lipedema have not yet been clarified.

Methods: A whole transcriptome analysis of subcutaneous tissue of lipedema stages I (n = 12), II (n = 9), and III (n = 8) compared with hypertrophied subcutaneous tissue (n = 4) was performed. Further data about hormonal substitution and body morphology were collected. The study is registered at ClinicalTrials.gov (NCT05861583).

Results: We identified several differentially expressed genes involved in mechanisms leading to the development of lipedema. Some genes, such as PRKG2, MEDAG, CSF1R, BICC1, ERBB4, and ACP5, are involved in adipogenesis, regulating the development of mature adipocytes from mesenchymal stem cells. Other genes, such as MAFB, C1Q, C2, CD68, CD209, CD163, CD84, BCAT1, and TREM2, are predicted to be involved in lipid accumulation, hypertrophy, and the inflammation process. Further genes such as SHTN1, SCN7A, and SCL12A2 are predicted to be involved in the regulation and transmission of pain.

Conclusions: In summary, the pathogenesis and development of lipedema might be caused by alterations in adipogenesis, inflammation, and extracellular matrix remodeling, leading to fibrosis and the formation of edema resulting in this painful disease. These processes differ from hypertrophied adipose tissue and may therefore play a main role in the formation of lipedema.

Fig. 1.

Graphical abstract. Biopsies from subcutaneous fat tissue of the thigh from patients with lipedema with different stages (study group) or hypertrophied fat tissue (control group) were obtained intraoperatively. The samples were processed and analyzed using NGS sequencing. The RNA expression differences between lipedema and the control group were then compared and the up- and down-regulated genes were shown in heatmaps. The altered gene expression pattern in lipedema patients provides information about which processes might differ. These include changes in adipogenesis, inflammation, and fibrosis of the subcutaneous tissue. This illustration was created by using Bioicons (https://bioicons.com/): sequence_histogram is licensed under CC0 by Marcel Tisch; nudeotide-t/a/c/g-0 is licensed under CC0 by Emmett Leddin; C-DNA is licensed under CC-BY 4.0 Unported by DBCLS, and the icon is modified in size; lllumina_miseq is licensed under CC-BY 4.0 Unported by DBCLS; tweezers_noS is licensed under CC-BY 4.0 Unported by DBCLS; microtube-dosed is licensed under CC-BY 4.0 Unported by DBLS, and the icon is modified by overlay; obese-female is licensed under CC-BY 3.0 Unported by Servier and modified by detail clipping; fat tissue is licensed under CC-BY 3.0 Unported by Servier.

Fig. 2.

Potential regulation of adipogenesis in lipedema. The signaling pathway of adipogenesis displays the difference of mesenchymal stem cells to mature adipocytes via known signaling cascades. Known regulating factors of adipogenesis are marked in black. Factors that might be involved in the development of lipedema based on our data analysis were shown in red and their activating or inhibiting effects were labeled accordingly.

Fig. 3.

Potential pathological processes of lipedema. The process of fatty tissue lipedema might be caused by changes in cell size, impaired lipid accumulation, lymphangiogenesis and angiogenesis, inflammation and ECM remodeling, and fibrosis. These processes are fired by hypoxia, vascular dysfunction, and immune response, which contributes to the development of a chronic inflammatory process. This ultimately leads to changes in the ECM resulting in fibrosed tissue with increased pain. Genes that are involved in the development of lipedema via these pathological processes based on our data analysis are shown in red.