Project: Mechanisms underlying the development and clinical manifestations of Lipedema: Lessons from a single-cell approach

Principal Investigator: Prof. Matthias Blüher, MD
Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG)
Helmholtz Zentrum München
University of Leipzig and University Hospital
Leipzig, Germany

Medical Department III – Endocrinology, Nephrology, Rheumatology
University of Leipzig Medical Center
Leipzig, Germany

Co-Principal Investigator: Pamela A. Nono Nankam, PhD
Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG)
Helmholtz Zentrum München
University of Leipzig and University Hospital
Leipzig, Germany

Summary

This project employs a high-throughput single-nuclei RNA-sequencing approach to investigate the biology of subcutaneous adipose tissue (SAT) in Lipedema. The objective is to assess modifications in cellular composition, subpopulations, and function within SAT that may contribute to changes in tissue structure, extracellular matrix, and transcriptomic profiles. These alterations might be responsible for Lipedema development and associated clinical manifestations.

Background

The current lack of data and limited understanding of the underlying mechanisms involved in the development of Lipedema, even several decades after its initial description, underscores the critical necessity for additional evidence-based studies. Our previous research has identified differences in metabolic and systemic profiles between Lipedema and obesity, despite both conditions being characterized by excessive SAT accumulation. However, the presence of pain in Lipedema fat and the resistance to SAT mass reduction through various weight loss measures suggest that the mechanisms of SAT accumulation and biology in Lipedema are distinct and to be elucidated.

Methodology

The study will include women diagnosed with Lipedema and a control group without lipedema, matched for BMI and waist-to-height ratio. Participants aged between 18 and 70 years, with a BMI ranging from 25 to 40 kg/m2, will be eligible for inclusion.

To investigate the cellular composition and function of SAT in lipedema, different approaches will be employed, including single-nuclei and whole-tissue RNA sequencing (snRNAseq), histological analyses and ex-vivo experiments. These approaches aim to identify distinct adipose tissue cell populations, their structure and function, as well as to determine pathways involved in the change of adipose tissue biology in lipedema.

Finally, using the generated data, exploratory analyses will be conducted to identify potential biomarkers and genes associated with lipedema through bioinformatics tools.

Expected outcomes

By utilizing unbiased and high-throughput methods, we anticipate to map three SAT depots (arm, abdomen and thigh) in lipedema, which will allow discerning the cell types involved in, or affected by, the persistent and excessive fat accumulation and related pain. Furthermore, we hypothesize the maintenance of adipose-specific insulin sensitivity as a potential reason for continuous excessive fat storage in lipedema without insulin resistance development. Ultimately, we expect to identify lipedema-specific biomolecules or genes that could serve as initial clinical markers for accurate diagnosis and differentiation from obesity.

Practical implementations of results

The resulting outcomes will enhance understanding of lipedema tissue at the cellular and molecular levels, and thereby advance lipedema research by identifying specific pathways and mechanisms involved in its development. This could open up possibilities for targeting excessive fat accumulation and pain through novel therapeutic approaches. Ultimately, these advancements have the potential to enhance patient care and treatment outcomes for individuals with lipedema, while also contributing to the broader understanding of the condition and inspiring further investigations in the field.

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