Lipedema and the Potential Role of Estrogen in Excessive Adipose Tissue Accumulation

Abstract

Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose tissue predominantly in the lower body. The onset of lipedema pathophysiology is thought to occur during periods of hormonal fluctuation, such as puberty, pregnancy, or menopause. Although the identification and characterization of lipedema have improved, the underlying disease etiology remains to be elucidated. Estrogen, a key regulator of adipocyte lipid and glucose metabolism, and female-associated body fat distribution are postulated to play a contributory role in the pathophysiology of lipedema. Dysregulation of adipose tissue accumulation via estrogen signaling likely occurs by two mechanisms: (1). altered adipocyte estrogen receptor distribution (ERα/ERß ratio) and subsequent metabolic signaling and/or (2). increased release of adipocyte-produced steroidogenic enzymes leading to increased paracrine estrogen release. These alterations could result in increased activation of peroxisome proliferator-activated receptor γ (PPARγ), free fatty acid entry into adipocytes, glucose uptake, and angiogenesis while decreasing lipolysis, mitochondriogenesis, and mitochondrial function. Together, these metabolic alterations would lead to increased adipogenesis and adipocyte lipid deposition, resulting in increased adipose depot mass. This review summarizes research characterizing estrogen-mediated adipose tissue metabolism and its possible relation to excessive adipose tissue accumulation associated with lipedema.

A Scoping Review of Available Tools in Measurement of the Effectiveness of Conservative Treatment in Lipoedema

“…Potentially, there is a disbalance between oestrogen receptors (ER alpha and ER beta) in adipose tissue of lipoedema affected certain areas, occurring as a result of faulty expression of oestrogen receptors. It can explain the abnormal proliferation of adipose tissue in the affected areas [ 6 , 7 ].…”

Multi-level analysis of adipose tissue reveals the relevance of perivascular subpopulations and an increased endothelial permeability in early-stage lipedema

“…To our knowledge, the demonstration of increased ZNF423 expression in lipedema-derived SVF, EC and PC provides for the first time a potential link of estrogen to preadipocyte commitment in lipedema. Katzer et al recently proposed that estrogen-mediated dysregulation of lower body fat accumulation in lipedema might be explained by a higher ERα/ERβ ratio or an increased production of steroidogenic enzymes, like aromatase, leading to a paracrine signaling and ERα activation among local adipocytes [12]. Indeed, we observed increased aromatase (CYP19A1) gene expression in lipedema thigh AT, which is also roughly reflected in the SVF, a cell population that does not contain mature adipocytes.…”

“…Bauer et al reported an increased IL-8 concentration in CM of undifferentiated ASC from lipedema patients, which decreased upon adipogenic stimulation to the equally low levels of the control cells [46]. The significant reduction of IL-8 secreted by lipedema SVF may correlate with higher local estradiol levels, which we and others have implicated with lipedema formation [12]. In the context of breast cancer cell lines, IL-8 has been identified as a regulatory target of estrogen receptor α and inhibited IL-8 levels as key factor for limited angiogenesis and tumor invasion [52].…”

“…Therefore, estrogen has been suggested as the key regulator of the excessive adipose tissue accumulation in lipedema. Since, estrogen directly affects lipid metabolism in white adipose tissue, mainly through its estrogen receptors (ER) alpha and beta, it has been hypothesized that altered ER expression and signaling might be involved in lipedema onset [12]. Different studies have postulated a correlation of the onset and progression of lipedema with microangiopathy, lymphangiopathy, adipocyte hyperplasia/hypertrophy, tissue hypoxia, fibrosis, and macrophage infiltration, without the causal triggering factors being found or the pathophysiological significance of the hormones being clarified [13][14][15][16][17][18][19].…”

Current Mechanistic Understandings of Lymphedema and Lipedema: Tales of Fluid, Fat, and Fibrosis

“…[ 2 , 30 , 36 , 37 , 38 ]. Finally, lipedema almost exclusively occurs in females, has a strong familial history, and symptoms onset around periods of hormonal change (i.e., puberty, pregnancy, menopause), suggestive of estrogen-driven disease mechanisms and heritable traits [ 39 , 40 ].…”