17α-Estradiol Modulates IGF1 and Hepatic Gene Expression in a Sex-Specific Manner

Abstract

Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of most conserved biological pathways that regulates aging across species. 17α-estradiol (17α-E2), a diastereomer of 17β-estradiol (17β-E2), was recently found to elicit health benefits, including improved insulin-sensitivity, and extend longevity exclusively in male mice. Given that 17β-E2 is known to modulate somatotropic signaling in females through actions in the pituitary and liver, we hypothesized that 17α-E2 may be modulating the somatotropic axis in males, thereby contributing to health benefits. Herein, we demonstrate that 17α-E2 increases hepatic IGF1 production in male mice without inducing any changes in pulsatile GH secretion. Using growth hormone receptor knockout (GHRKO) mice, we subsequently determined that the induction of hepatic IGF1 by 17α-E2 is dependent upon GH signaling in male mice, and that 17α-E2 elicits no effects on IGF1 production in female mice. We also determined that 17α-E2 failed to feminize the hepatic transcriptional profile in normal (N) male mice, as evidenced by a clear divergence between the sexes, regardless of treatment. Conversely, significant overlap in transcriptional profiles was observed between sexes in GHRKO mice, and this was unaffected by 17α-E2 treatment. Based on these findings, we propose that 17α-E2 acts as a pleiotropic pathway modulator in male mice by uncoupling IGF1 production from insulin sensitivity. In summary, 17α-E2 treatment upregulates IGF1 production in wild-type (and N) male mice in what appears to be a GH-dependent fashion, while no effects in female IGF1 production are observed following 17α-E2 treatment

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

“…However, the dose of 17α-E2 used in the vast majority of these studies, does not induce dramatic feminization of the sex hormone profiles in male mice ( Stout et al, 2017b ), which leads us to speculate that 17a-E2 is acting in a direct manner through ERα rather than indirectly through androgen modulation. Furthermore, studies in male rodents ( Livingstone et al, 2015 ; Dowman et al, 2013 ) and humans Wei et al, 2019 demonstrate that 5α-reductase inhibition or deficiency increases insulin resistance and hepatic steatosis and fibrosis, which are contradictory to the effects of 17α-E2 treatment in all of our studies utilizing male mice ( Stout et al, 2017b ; Steyn et al, 2018 ; Miller, 2020 ; Sidhom et al, 2020 ). Despite these contrasting observations, the studies by Garratt et al do provide important insights into the interconnected and underappreciated relationship between androgen- and estrogen-signaling pathways and their roles in metabolism and aging.…”

Towards Understanding the Direct and Indirect Actions of Growth Hormone in Controlling Hepatocyte Carbohydrate and Lipid Metabolism

“…These sex-dependent differences in gene expression are due, in part, to differential actions of the GH pattern on STAT5 DNA binding to gene promoters, as well as STAT5-dependent alteration in DNA methylation patterns [24,28,29]. In addition, estrogens regulate hepatic gene expression (including IGF1) dependent and independent of alterations in GH release [30,31]. Therefore, with respect to understanding the role GH plays on liver metabolism, caution should be used when extrapolating findings between males and females.…”

“…As indicated above, GH-mediated lipolysis generates NEFA, which serves as a substrate for mitochondrial β (fatty acid) oxidation and ATP generation. In acromegalic subjects, hepatic lipid content is low and is associated with an increase in hepatic ATP synthesis rate as assessed by 31 P/ 1 H-7-T MR spectroscopy [171]. In addition, aHepGHRkd mice under basal conditions suppress the hepatic expression of carnitine palmitoyltransferase 1A (Cpt1a), independent of changes NEFA levels, or enhanced hepatic insulin signaling [59].…”

Growth Hormone and Aging: New Findings

“…Treatment of mice with Estradiol 17 alpha (17αE2; a weakly estrogenic compound, distinct from the main female sex hormone, estradiol 17 beta) produces health benefits such as improved insulin sensitivity and extends longevity in males but not in females [ 59 ]. We found that treatment with 17αE2 increased hepatic IGF-I production exclusively in males [ 60 ]. Surprisingly, this effect did not involve modifications of the pattern of GH release or “feminization” of the hepatic transcriptional profile.…”

“…Surprisingly, this effect did not involve modifications of the pattern of GH release or “feminization” of the hepatic transcriptional profile. However, this effect of 17αE2 on IGF-I production was GH-dependent since it was not elicited in GH-resistant Ghr-/- mice [ 60 ]. Apparently, anti-aging effects of 17αE2 in male mice are GH-dependent and involve alterations in IGF-I, but not GH dynamics.…”