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

2020 ◽  
Author(s):  
Shivani N. Mann ◽  
Niran Hadad ◽  
Molly Nelson-Holte ◽  
Alicia R. Rothman ◽  
Roshini Sathiaseelan ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Chronic Diseases ◽  
Transcriptional Activation ◽  
Estrogen Receptor Α ◽  
Metabolic Parameters ◽  
Metabolic Effects ◽  
Male Rats ◽  
Male Mice ◽  
Dietary Interventions ◽  
Estradiol Treatment

ABSTRACTMetabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 acts primarily through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.

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

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Shivani N Mann ◽  
Niran Hadad ◽  
Molly Nelson Holte ◽  
Alicia R Rothman ◽  
Roshini Sathiaseelan ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Chronic Diseases ◽  
Transcriptional Activation ◽  
Estrogen Receptor Α ◽  
Metabolic Parameters ◽  
Metabolic Effects ◽  
Male Rats ◽  
Male Mice ◽  
Dietary Interventions ◽  
Estradiol Treatment

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.

scholarly journals Testosterone Prevents Cutaneous Ischemia and Necrosis in Males Through Complementary Estrogenic and Androgenic Actions

2017 ◽  
Vol 37 (5) ◽  
pp. 909-919 ◽  
Author(s):  
Caroline Chenu ◽  
Marine Adlanmerini ◽  
Frederic Boudou ◽  
Elodie Chantalat ◽  
Anne-Laure Guihot ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Direct Action ◽  
Skin Flap ◽  
Treatment Strategies ◽  
Estrogen Receptor Α ◽  
Male Mice ◽  
Resistance Arteries ◽  
Estradiol Treatment ◽  
Impaired Wound Healing ◽  
17Β Estradiol

Objective— Chronic nonhealing wounds are a substantial medical concern and are associated with morbidity and mortality; thus, new treatment strategies are required. The first step toward personalized/precision medicine in this field is probably in taking sex differences into account. Impaired wound healing is augmented by ischemia, and we previously demonstrated that 17β-estradiol exerts a major preventive effect against ischemia-induced skin flap necrosis in female mice. However, the equivalent effects of testosterone in male mice have not yet been reported. We then investigated the role of steroid hormones in male mice using a skin flap ischemia model. Approach and Results— Castrated male mice developed skin necrosis after ischemia, whereas intact or castrated males treated with testosterone were equally protected. Testosterone can (1) activate the estrogen receptor after its aromatization into 17β-estradiol or (2) be reduced into dihydrotestosterone, a nonaromatizable androgen that activates the androgen receptor. We found that dihydrotestosterone protected castrated wild-type mice by promoting skin revascularization, probably through a direct action on resistance arteries, as evidenced using a complementary model of flow-mediated outward remodeling. 17β-estradiol treatment of castrated male mice also strongly protected them from ischemic necrosis through the activation of estrogen receptor-α by increasing skin revascularization and skin survival. Remarkably, 17β-estradiol improved skin survival with a greater efficiency than dihydrotestosterone. Conclusions— Testosterone provides males with a strong protection against cutaneous necrosis and acts through both its estrogenic and androgenic derivatives, which have complementary effects on skin survival and revascularization.

Membrane estrogen receptor α is essential for estrogen signaling in the male skeleton

2018 ◽  
Vol 239 (3) ◽  
pp. 303-312 ◽  
Author(s):  
H H Farman ◽  
K L Gustafsson ◽  
P Henning ◽  
L Grahnemo ◽  
V Lionikaite ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Areal Bone Mineral Density ◽  
Male Mice ◽  
Mineral Density ◽  
Intact Male ◽  
Trabecular Thickness ◽  
Total Body

The importance of estrogen receptor α (ERα) for the regulation of bone mass in males is well established. ERα mediates estrogenic effects both via nuclear and membrane-initiated ERα (mERα) signaling. The role of mERα signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERα signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERα to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (µCT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mERα is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.

scholarly journals Dietary essential amino acids restore liver metabolism in ovariectomized mice via hepatic estrogen receptor α

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sara Della Torre ◽  
Valeria Benedusi ◽  
Giovanna Pepe ◽  
Clara Meda ◽  
Nicoletta Rizzi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Estrogen Receptor ◽  
Weight Gain ◽  
Molecular Mechanisms ◽  
Liver Lipid ◽  
Essential Amino Acids ◽  
Estrogen Receptor Α ◽  
Metabolic Effects ◽  
Ovariectomized Mice ◽  
Dietary Treatments

AbstractIn female mammals, the cessation of ovarian functions is associated with significant metabolic alterations, weight gain, and increased susceptibility to a number of pathologies associated with ageing. The molecular mechanisms triggering these systemic events are unknown because most tissues are responsive to lowered circulating sex steroids. As it has been demonstrated that isoform alpha of the estrogen receptor (ERα) may be activated by both estrogens and amino acids, we test the metabolic effects of a diet enriched in specific amino acids in ovariectomized (OVX) mice. This diet is able to block the OVX-induced weight gain and fat deposition in the liver. The use of liver-specific ERα KO mice demonstrates that the hepatic ERα, through the control of liver lipid metabolism, has a key role in the systemic response to OVX. The study suggests that the liver ERα might be a valuable target for dietary treatments for the post-menopause.

Salutary effects of 17β-estradiol on T-cell signaling and cytokine production after trauma-hemorrhage are mediated primarily via estrogen receptor-α

2007 ◽  
Vol 292 (6) ◽  
pp. C2103-C2111 ◽  
Author(s):  
Takao Suzuki ◽  
Tomoharu Shimizu ◽  
Huang-Ping Yu ◽  
Ya-Ching Hsieh ◽  
Mashkoor A. Choudhry ◽  
...  
Keyword(s):  
T Cells ◽  
Estrogen Receptor ◽  
T Cell ◽  
Signaling Pathways ◽  
Cytokine Production ◽  
Estrogen Receptor Α ◽  
Male Rats ◽  
17Β Estradiol ◽  
Ifn Γ ◽  
Cell Cytokine Production

Although 17β-estradiol (E2) administration following trauma-hemorrhage prevents the suppression in splenocyte cytokine production, it remains unknown whether the salutary effects of 17β-estradiol are mediated via estrogen receptor (ER)-α or ER-β. Moreover, it is unknown which signaling pathways are involved in 17β-estradiol's salutary effects. Utilizing an ER-α- or ER-β-specific agonist, we examined the role of ER-α and ER-β in E2-mediated restoration of T-cell cytokine production following trauma-hemorrhage. Moreover, since MAPK, NF-κB, and activator protein (AP)-1 are known to regulate T-cell cytokine production, we also examined the activation of MAPK, NF-κB, and AP-1. Male rats underwent trauma-hemorrhage (mean arterial pressure 40 mmHg for 90 min) and fluid resuscitation. ER-α agonist propyl pyrazole triol (PPT; 5 μg/kg), ER-β agonist diarylpropionitrile (DPN; 5 μg/kg), 17β-estradiol (50 μg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, splenic T cells were isolated, and their IL-2 and IFN-γ production and MAPK, NF-κB, and AP-1 activation were measured. T-cell IL-2 and IFN-γ production was decreased following trauma-hemorrhage, and this was accompanied with a decrease in T-cell MAPK, NF-κB, and AP-1 activation. PPT or 17β-estradiol administration following trauma-hemorrhage normalized those parameters, while DPN administration had no effect. Since PPT, but not DPN, administration following trauma-hemorrhage was as effective as 17β-estradiol in preventing the T-cell suppression, it appears that ER-α plays a predominant role in mediating the salutary effects of 17β-estradiol on T cells following trauma-hemorrhage, and that such effects are likely mediated via normalization of MAPK, NF-κB, and AP-1 signaling pathways.

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