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Impact of Estrogens on the Regulation of White, Beige, and Brown Adipose Tissue Depots

Gabriel B. Bernasochi, James R. Bell, Evan R. Simpson, Lea M.D. Delbridge, Wah Chin Boon

10.1002/cphy.c180009

Source: Volume 9, Issue 2, April 2019

Published online: March 2019

Full Article on Wiley Online Library



ABSTRACT

As adipose tissue depots are active endocrine organs, they secrete a variety of hormones (including estrogens from white adipose) and inflammatory mediators, which have important implications in numerous obesity‐associated diseases. Adipose tissues are broadly characterized as consisting of white, beige, and brown depot types. The endocrine, metabolic, and inflammatory profiles of adipose are depot dependent and influenced by the estrogenic and androgenic status of the adipose tissue. Estrogen receptors mediate both the genomic and nongenomic actions of estrogens and are expressed in the brain, heart, and other peripheral tissues. All three known estrogen receptor α (ERα) and estrogen receptor β (ERβ), and the G‐protein coupled estrogen receptor (GPER/GPR30) are expressed in white adipose and can modulate adipose mass. Expression of each receptor is dependent on depot location, adipose cell type, and estrogen levels. Estrogen receptor expression profiles in beige and brown adipocytes are less well established. This review will discuss the effects of estrogens on the differential deposition of the major adipose tissues and the impact of estrogens within white adipose depots. © 2019 American Physiological Society. Compr Physiol 9:457‐475, 2019.

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Figure 1. Figure 1. The biosynthesis of estrogens in white adipose tissues from androgen steroid precursors. The sources of these androgens are listed in parentheses. 17α‐estradiol synthesis has been confirmed in other tissues such as the brain and is speculated to occur in adipose. Estrogens and other steroid hormones are also able to enter white adipose tissue from circulating blood. Abbreviations: 3β‐HSD2, 3β‐hydroxysteroid dehydrogenase type 2; 17α‐HSD3, 17β‐hydroxysteroid dehydrogenase type 3; 17β‐HSD1, 17β‐hydroxysteroid dehydrogenase type 1; 17β‐HSD2, 17β‐hydroxysteroid dehydrogenase type 2; 17β‐HSD3, 17β‐hydroxysteroid dehydrogenase type 3; 17β‐HSD4, 17β‐hydroxysteroid dehydrogenase type 4; 16α‐OH‐DHEA, 16α‐hydroxydehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; DHT, 5α‐dihydrotestosterone.
Figure 2. Figure 2. Estrogen production in women. Premenopausally, ovarian estrogens act in an endocrine fashion to elicit signaling in peripheral organs. Postmenopausally, there is a shift to local estrogen production in extragonadal tissues, which exert paracrine and autocrine actions. This shift is usually accompanied by phenotypic change in adipose depot predominance from subcutaneous to visceral accumulation. Extragonadal aromatase expression and activity determine estrogen synthesis and are regulated by tissue‐specific gene promoters and signaling intermediates such as PGE2, cAMP, cytokines, and androgens. This allows for fine modulation of tissue androgen‐estrogen synthesis. Estrogen receptors ERα, ERβ, and G‐protein coupled estrogen receptor (GPER) are expressed in visceral and subcutaneous adipose (110), brain (28,237), bone (24,42), and heart (57,139). These three receptors can have different and even opposing actions on tissues. The specific roles of estrogen receptors in adipose tissues are discussed in the text. Abbreviations: 5α‐DHT, 5α‐Dihydrotestosterone; DHEA, Dehydroepiandrosterone; DHEAS, Dehydroepiandrosterone sulfate; cAMP, cyclic adenosine monophosphate; FSH, follicle stimulating hormone; ER, estrogen receptor PGE2, prostaglandin E2.


Figure 1. The biosynthesis of estrogens in white adipose tissues from androgen steroid precursors. The sources of these androgens are listed in parentheses. 17α‐estradiol synthesis has been confirmed in other tissues such as the brain and is speculated to occur in adipose. Estrogens and other steroid hormones are also able to enter white adipose tissue from circulating blood. Abbreviations: 3β‐HSD2, 3β‐hydroxysteroid dehydrogenase type 2; 17α‐HSD3, 17β‐hydroxysteroid dehydrogenase type 3; 17β‐HSD1, 17β‐hydroxysteroid dehydrogenase type 1; 17β‐HSD2, 17β‐hydroxysteroid dehydrogenase type 2; 17β‐HSD3, 17β‐hydroxysteroid dehydrogenase type 3; 17β‐HSD4, 17β‐hydroxysteroid dehydrogenase type 4; 16α‐OH‐DHEA, 16α‐hydroxydehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; DHT, 5α‐dihydrotestosterone.


Figure 2. Estrogen production in women. Premenopausally, ovarian estrogens act in an endocrine fashion to elicit signaling in peripheral organs. Postmenopausally, there is a shift to local estrogen production in extragonadal tissues, which exert paracrine and autocrine actions. This shift is usually accompanied by phenotypic change in adipose depot predominance from subcutaneous to visceral accumulation. Extragonadal aromatase expression and activity determine estrogen synthesis and are regulated by tissue‐specific gene promoters and signaling intermediates such as PGE2, cAMP, cytokines, and androgens. This allows for fine modulation of tissue androgen‐estrogen synthesis. Estrogen receptors ERα, ERβ, and G‐protein coupled estrogen receptor (GPER) are expressed in visceral and subcutaneous adipose (110), brain (28,237), bone (24,42), and heart (57,139). These three receptors can have different and even opposing actions on tissues. The specific roles of estrogen receptors in adipose tissues are discussed in the text. Abbreviations: 5α‐DHT, 5α‐Dihydrotestosterone; DHEA, Dehydroepiandrosterone; DHEAS, Dehydroepiandrosterone sulfate; cAMP, cyclic adenosine monophosphate; FSH, follicle stimulating hormone; ER, estrogen receptor PGE2, prostaglandin E2.
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Teaching Material

G. B. Bernasochi, J. R. Bell, E. R. Simpson, L. M. D. Delbridge, W. C. Boon. Impact of Estrogens on the Regulation of White, Beige, and Brown Adipose Tissue Depots. Compr Physiol 9: 2019, 457-475.

Didactic Synopsis

Major Teaching Points:

  • Estrogens are a group of hormones (e.g. 17β-estradiol, estrone, estriol) that have an 18-carbon backbone structure derived from cholesterol; their immediate precursors are androgens.
  • The conversion of androgens to estrogens is catalyzed by the enzyme aromatase. The expression of aromatase is highly regulated and controls the levels of estrogens secreted.
  • Estrogens are not just female hormones responsible for reproduction but also regulate energy homeostasis via influencing the functions of adipose tissues.
  • Estrogens act in endocrine (travel in the blood stream and modulate distant targets), paracrine (diffuse from the cell and modulate neighbor cells) and autocrine (modulate the origin cell of synthesis) manners.
  • White and brown adipose tissues are for energy and body temperature homeostasis respectively. The white adipose tissues are in close proximity to other organs and may regulate the functions of these organs; and can change into beige adipose tissues in response to the cold.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: Estrogen production in fat tissue is dependent on gonadal (and adrenal) androgens in the blood. The sources of these androgens are listed in parentheses. When androgens enter preadipocytes/stromal mesenchymal cells within fat depots, they can be converted to different types of androgens (namely, 5α-DHT, Testosterone, Androstenedione, DHEAS) and also into estrogens (estrone, 17β-estradiol and estriol). Note that 5α-DHT is a potent androgen which cannot be converted into an estrogen by aromatase. Although significant androgen to estrogen synthesis occurs in fat, estrogens are also able to enter fat tissue from circulating blood – which are of ovarian origin. Abbreviations: 5α-DHT, 5α-Dihydrotestosterone; DHEA, Dehydroepiandrosterone; DHEAS, Dehydroepiandrosterone sulfate; cAMP, cyclic adenosine monophosphate; FSH, follicle stimulating hormone; ER, estrogen receptor PGE2, prostaglandin E2.

Figure 2 Teaching points: Before menopause, estrogens produced in the ovaries are important in mediating estrogenic signaling in non-gonadal tissues such in the brain, adipose, breast, bone and heart (endocrine signaling). During menopause, ovarian estrogen production ceases and estrogens are predominantly produced in non-gonadal tissues and these estrogens can act within the estrogen-producing tissue (autocrine) and on other nearby tissues (paracrine). This is accompanied by a shift from predominantly subcutaneous adipose to visceral adipose deposition which is also more similar to the male phenotype. Within these tissues three types of estrogen receptor are functionally responsive to estrogens. These receptors can often have opposing actions and their function is typically dependent on tissue type. The gene promotor regulators of aromatase activity and expression determine the degree of estrogen synthesis from androgen precursors in these tissues. Aromatase gene promotors are tissue-specific and allow for fine regulation of aromatase expression.

 


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Article Title: Impact of Estrogens on the Regulation of White, Beige, and Brown Adipose Tissue Depots
 

How to Cite

Gabriel B. Bernasochi, James R. Bell, Evan R. Simpson, Lea M.D. Delbridge, Wah Chin Boon. Impact of Estrogens on the Regulation of White, Beige, and Brown Adipose Tissue Depots. Compr Physiol 2019, 9: 457-475. doi: 10.1002/cphy.c180009