Key signaling networks are dysregulated in patients with the adipose tissue disorder, lipedema

• DOI: 10.1038/s41366-021-01002-1
• Publication Date: 2021-11-11T07:04:59Z
• Authors: Musarat Ishaq; Nadeeka Bandara; Steven Morgan; Cameron Nowell; Ahmad M. Mehdi; Ruqian Lyu; Davis McCarthy; Dovile Anderson; Darren J. Creek; Marc G. Achen; Ramin Shayan; Tara Karnezis
• Keywords: 0301 basic medicine; Adipogenesis; Lipedema; 610; Cell Differentiation; Lipids; Article; 3. Good health; 03 medical and health sciences; Adipose Tissue; 616; Adipocytes; Humans

Abstract Objectives Lipedema, a poorly understood chronic disease of adipose hyper-deposition, is often mistaken for obesity and causes significant impairment to mobility quality-of-life. To identify molecular mechanisms underpinning lipedema, we employed comprehensive omics-based comparative analyses whole tissue, adipocyte precursors (adipose-derived stem cells (ADSCs)), adipocytes from patients with or without lipedema. Methods We compared whole-tissues, ADSCs, body mass index–matched lipedema ( n = 14) unaffected 10) using global lipidomic metabolomic analyses, transcriptional profiling, functional assays. Results Transcriptional profiling revealed >4400 differences in altered levels mRNAs involved critical signaling cell function-regulating pathways (e.g., lipid metabolism cell-cycle/proliferation). Functional assays showed accelerated ADSC proliferation differentiation Profiling >900 changes composition >600 differentially metabolites. ADSCs non-lipedema differential expression >3400 genes including some extracellular matrix cell-cycle/proliferation pathways. One upregulated gene Bub1 , encodes cell-cycle regulator, central the kinetochore complex, which regulates several histone proteins proliferation. Downstream analysis demonstrated enhanced activation H2A, key driver target. Critically, hyperproliferation exhibited by was inhibited small molecule inhibitor 2OH-BNPP1 CRISPR/Cas9-mediated depletion. Conclusion found expression, metabolite profiles, non-affected controls. that dysregulated drives increased suggesting potential mechanism adipogenesis Importantly, our characterization networks driving identifies targets, Bub1, novel therapeutics.