Abstract
ObjectivesLipedema, a poorly understood chronic disease of adipose hyper-deposition, is often mistaken for obesity and causes significant impairment to mobility and quality-of-life. To identify molecular mechanisms underpinning lipedema, we employed comprehensive omics-based comparative analyses of whole tissue, adipocyte precursors (adipose-derived stem cells (ADSCs)), and adipocytes from patients with or without lipedema.MethodsWe compared whole-tissues, ADSCs, and adipocytes from body mass index–matched lipedema (n = 14) and unaffected (n = 10) patients using comprehensive global lipidomic and metabolomic analyses, transcriptional profiling, and functional assays.ResultsTranscriptional profiling revealed >4400 significant differences in lipedema tissue, with altered levels of mRNAs involved in critical signaling and cell function-regulating pathways (e.g., lipid metabolism and cell-cycle/proliferation). Functional assays showed accelerated ADSC proliferation and differentiation in lipedema. Profiling lipedema adipocytes revealed >900 changes in lipid composition and >600 differentially altered metabolites. Transcriptional profiling of lipedema ADSCs and non-lipedema ADSCs revealed significant differential expression of >3400 genes including some involved in extracellular matrix and cell-cycle/proliferation signaling pathways. One upregulated gene in lipedema ADSCs, Bub1, encodes a cell-cycle regulator, central to the kinetochore complex, which regulates several histone proteins involved in cell proliferation. Downstream signaling analysis of lipedema ADSCs demonstrated enhanced activation of histone H2A, a key cell proliferation driver and Bub1 target. Critically, hyperproliferation exhibited by lipedema ADSCs was inhibited by the small molecule Bub1 inhibitor 2OH-BNPP1 and by CRISPR/Cas9-mediated Bub1 gene depletion.ConclusionWe found significant differences in gene expression, and lipid and metabolite profiles, in tissue, ADSCs, and adipocytes from lipedema patients compared to non-affected controls. Functional assays demonstrated that dysregulated Bub1 signaling drives increased proliferation of lipedema ADSCs, suggesting a potential mechanism for enhanced adipogenesis in lipedema. Importantly, our characterization of signaling networks driving lipedema identifies potential molecular targets, including Bub1, for novel lipedema therapeutics.
Highlights
Lipedema is a poorly understood, chronic disease characterized by bilaterally symmetrical deposition of abnormal adipose tissue, predominantly in the legs and variably in the arms [1, 2]
Defective lipid catabolic pathways are involved in the pathogenesis of several metabolic diseases [49]. Neutral lipids, such as triglycerides, are less likely to promote metabolic disorders compared to other lipids classes such as sphingolipids and GPLs [50, 51], which have been documented to be involved in several metabolic diseases [52]
An example of the distinct nature of lipedema adipose tissue is illustrated by our discovery of metabolic differences in lipedema relating to levels of fatty acids and their conjugates that included GPLs that are metabolites known to regulate cell-cycle events in cell growth, and to enhance cell size and proliferation [53, 54]; notably, GPL inhibition can reduce cell proliferation [55, 56]
Summary
Lipedema is a poorly understood, chronic disease characterized by bilaterally symmetrical deposition of abnormal adipose tissue, predominantly in the legs and variably in the arms [1, 2]. The classification of lipedema is based on the distribution of adipose tissue and on the severity of the disease (Stages I, II, III, and IV) [3] (Supplementary Fig. 1a). Excessive accumulation of WAT in abdominal organs (visceral adipose tissue) and subcutaneous regions disrupts metabolic homeostasis and likely drives metabolic disorders [4, 5]. Patients accumulate excessive amounts of subcutaneous WAT, predominately in the legs [2]. Lipedema is often confused with obesity, lymphedema, lipodystrophies, and other fat disorders [1] and currently is diagnosed clinically. Palpation and intraoperative examination of lipedema fat reveals a nodular structure and consistency, in contrast to normal fat that is smooth
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