Stress, Sex, and Sugar: Glucocorticoids and Sex-Steroid Crosstalk in the Sex-Specific Misprogramming of Metabolism

Abstract

<jats:title>Abstract</jats:title> <jats:p>Early-life exposures to environmental insults can misprogram development and increase metabolic disease risk in a sex-dependent manner by mechanisms that remain poorly characterized. Modifiable factors of increasing public health relevance, such as diet, psychological stress, and endocrine-disrupting chemicals, can impact glucocorticoid receptor (GR) signaling during gestation and lead to sex-specific postnatal metabolic derangements. Evidence from humans and animal studies indicate that glucocorticoids crosstalk with sex steroids by several mechanisms in multiple tissues and can impact sex steroid-dependent developmental processes. Nonetheless, glucocorticoid-sex steroid crosstalk has not been considered in the glucocorticoid-induced misprogramming of metabolism. Herein we review what is known about the mechanisms by which glucocorticoids crosstalk with estrogen, androgen, and progestogen action. We propose that glucocorticoid-sex steroid crosstalk is an understudied mechanism of action that requires consideration when examining the developmental misprogramming of metabolism, especially when assessing sex-specific outcomes.</jats:p>

Adipose Tissue and Endocrine-Disrupting Chemicals: Does Sex Matter?

“…Indeed, adult males had impaired glucose tolerance but no changes of adiposity if exposed perinatally while they showed enhanced body weight, adiposity, and insulin resistance if exposed during adulthood [ 194 ]. Consistent with the distinct regulation of the adipose tissue by glucocorticoids in males and females, female mice exposed perinatally to TF showed enhanced systemic insulin sensitivity, reduced adiposity and normal hepatic gluconeogenesis [ 193 ]. However, others demonstrated that TF impacted mitochondrial metabolism but failed to demonstrate obesogenic effects of TF [ 195 ].…”

“…In vitro experiments using the 3T3-L1 cell culture model demonstrated that TF had GR-agonist activities [ 130 ]. Moreover, perinatal exposure to TF showed sex-specific adverse effects on the adipose tissue [ 192 ] which may have epigenetic basis [ 193 ] at least in males (females had not been studied). Indeed, adult males had impaired glucose tolerance but no changes of adiposity if exposed perinatally while they showed enhanced body weight, adiposity, and insulin resistance if exposed during adulthood [ 194 ].…”

Sex and Stress Steroid Crosstalk Reviewed: Give Us More

“…The importance of this steroid hormone crosstalk was comprehensively described in a recent publication by Daniel Ruiz, Vasantha Padmanabhan, and Robert Sargis [ 4 ]. In their review, the authors focus on metabolic (mis)programming during fetal development, and discuss that early overexposure to glucocorticoids (either exogenous, or as a consequence of stress) can disrupt sex steroid action later in life.…”

“…While much research focuses on androgens and estrogens, progesterone receptor signaling is often ignored but may in fact contribute to sex-differences in metabolism as well, as covered by Ruiz et al [ 4 ]. In fact, steroid hormone receptors—glucocorticoid, androgen, progesterone, and the mineralocorticoid receptors; and to a lesser extent the estrogen receptor-α and -β—are very similar in molecular structure.…”

“…It makes perfect sense that scientific societies and funding bodies advocate the use of both males and females in biomedical research—which is nowadays endorsed by many (e.g., Dutch Heart Foundation, NWO-Dutch Science Agenda, National Institutes of Health). We are pleased that the current review by Ruiz and colleagues [ 4 ] puts additional focus on the importance of sex-dependency and steroid hormone crosstalk, and points out the many underresearched aspects of sex differences in general, and steroid crosstalk in particular.…”