Project: Estrogen Signaling in Adipose Tissue Metabolism and Development of Lipedema

Principal Investigator: Bruce Alan Bunnell, PhD
University of North Texas Health Center
Fort Worth, TX

Summary

This research project will investigate the role that estrogen plays in the development of Lipedema. We will use adipose tissue-derived stem cells (ASCs) isolated from thigh fat (adipose) tissue obtained from non-Lipedema “control” and Lipedema patients to determine if inappropriate regulation of estrogen expression drives the disease. We will also measure the endogenous levels of estrogens in the blood and fat tissue of controls and Lipedema patients. These studies on lipidemic and control human samples will help us better understand the role of estrogen and highlight the importance of hormones that may contribute to the onset and progression of Lipedema.

Background

Estrogens and estrogen receptors (ERs) control the distribution of female body fat and metabolism. ERs are differentially expressed in the body fat in overweight-to-obese pre-menopausal women, indicating that estrogens have an effect on fat tissue distribution through ER signaling. ER alpha (ERα) signaling regulates ASC differentiation (ability to become a mature fat cell) and function while ER beta (ERβ) has direct anti-adipogenic effects on adipocytes, and it inhibits the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ), a key factor in fat production.

Estrogens also regulate leptin and lipoprotein lipase genes (LPL) and increase angiogenesis and vascular endothelial growth factor (VEGF) expression, a phenomenon observed in fat tissue of Lipedema patients. Thus, ASCs obtained from Lipedema patients might be regulated by estrogens resulting in adipocyte hypertrophy, as well as increased inflammation and fibrosis in AT.

Methodology

In this study, we will determine the estrogen levels in blood samples, adipose tissue and ASCs from 
non-Lipedema “control” and Lipedema patients. In the first part of the study, we will investigate the impact of 17-β-estradiol treatment (E2) on ASCs ability to differentiate into adipocytes and on the expression of the main extracellular matrix (ECM) proteins under normal and inflammatory conditions.

The data will be used to highlight the estrogen signaling pathway that is involved in stem cell proliferation and adipocyte differentiation as well as angiogenesis and fibrosis and potentially provide data about the progression of the disease.


In the second part of the study, we will determine the levels of the three forms of estrogen [estrone (E1), estradiol (E2), and estriol (E3)] in the blood of pre- and post-menopausal women with Lipedema as well as the levels of estrogen in adipose tissue. The research plan will include Lipedema patients from stage 1, 2 and 3 and 20 non-Lipedema participants with matched BMI, age, and hormonal status. The data obtained will provide extensive knowledge about the hormonal levels of women with Lipedema and will establish an association (if any) with the progression of the disease through studying the Lipedema stages.

Expected outcomes

The results from this study will define the role played by estrogen in the development of Lipedema and will help direct future studies on the correlation between hormones and adipogenesis in fat tissue. Additionally, the data generated will also contribute to the identification of potential biomarkers for Lipedema and probably the development of targeted therapy that might prevent the progression of this disease. Further, this study will determine the role of estrogen in Lipedema and offer new insights into Lipedema as a hormonal disease. 

Practical implementations of results

The results from this study will define the expression of estrogens in patients with different Lipedema stages which will allow researchers to better understand the role of hormones in the progression of the disease. The data from this study will also provide insights into the development of novel pharmacologic interventions in the future.

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