The Regulation of Adipose Tissue Health by Estrogens

Abstract

Obesity and its' associated metabolic diseases such as type 2 diabetes and cardiometabolic disorders are significant health problems confronting many countries. A major driver for developing obesity and metabolic dysfunction is the uncontrolled expansion of white adipose tissue (WAT). Specifically, the pathophysiological expansion of visceral WAT is often associated with metabolic dysfunction due to changes in adipokine secretion profiles, reduced vascularization, increased fibrosis, and enrichment of pro-inflammatory immune cells. A critical determinate of body fat distribution and WAT health is the sex steroid estrogen. The bioavailability of estrogen appears to favor metabolically healthy subcutaneous fat over visceral fat growth while protecting against changes in metabolic dysfunction. Our review will focus on the role of estrogen on body fat partitioning, WAT homeostasis, adipogenesis, adipocyte progenitor cell (APC) function, and thermogenesis to control WAT health and systemic metabolism.

Keywords: adipocyte progenitor cells; adipokines; estrogen; estrogen receptor; hypertrophy; metabolically healthy; ovariectomy; white adipose tissue.

Figure 1

Estrogen influence on adipose tissue expansion. White adipose tissue can expand through either hypertrophy, the swelling of individual adipocytes, or hyperplasia, the increase of adipocyte numbers. Hypertrophy is accompanied by a reduction in vascularization, increased inflammation, and promotes fibrosis. Hyperplasia maintains tissue health by facilitating vascularization, promoting anti-inflammatory signals and block fibrosis. Estrogen levels play a role in determining the type of expansion and location which shifts as estrogen decreases due to pharmacological drugs, medical procedures, and/or age. While normal estrogen levels result in hyperplastic subcutaneous adipose tissue growth, reduced estrogen leads to metabolically unhealthy hypertrophic visceral adipose tissue expansion.

Figure 2

Site-specific regulation of adipose tissue by estrogen. White adipose tissue homeostasis and expansion is influenced by estrogen. In pre-menopausal females, estrogen produced by the ovaries plays a major role in ERα/β signaling thus downregulating androgen receptors, leading to hyperplastic subcutaneous WAT expansion and decreased visceral adipogenesis. Post-menopausal women have a ∼95% reduction in circulating estrogen levels due to cessation of ovarian function, resulting in a stunted ERα/β activation, thus giving rise to metabolically unhealthy hypertrophic WAT expansion.

Figure 3

Adipocyte Lineage progression. Adipocyte stem cells can generate committed progenitors which can undergo adipogenesis to become lipid-laden adipocytes. Developmental fate mapping, flow cytometry, and single-cell sequencing methodologies have identified unique and overlapping markers for each step during lineage maturation. Estrogen has been shown to regulate various aspects of the adipocyte lineage progression and mature adipocyte function. Yet, estrogens role may vary depending on depot and sex.