Prenatal androgen exposure programs metabolic dysfunction in female mice

Polycystic ovary syndrome (PCOS) is a common fertility disorder with metabolic sequelae. Our laboratory previously characterized reproductive phenotypes in a prenatally androgenized (PNA) mouse model for PCOS. PNA mice exhibited elevated testosterone and LH levels, irregular estrous cycles, and neuroendocrine abnormalities suggesting increased central drive to the reproductive system. In this study, we examined metabolic characteristics of female PNA mice. PNA mice exhibited increased fasting glucose and impaired glucose tolerance (IGT) that were independent of age and were not associated with changes in body composition or peripheral insulin sensitivity. IGT was associated with defects in pancreatic islet function leading to an impaired response to high glucose, consistent with impaired insulin secretion. Exposure of isolated pancreatic islets to androgen in vitro demonstrated an impaired response to glucose stimulation similar to that in PNA mice, suggesting androgens may have activational in addition to organizational effects on pancreatic islet function. PNA mice also exhibited increased size of visceral adipocytes, suggesting androgen-programed differences in adipocyte differentiation and/or function. These studies demonstrate that in addition to causing reproductive axis abnormalities, in utero androgen exposure can induce long-term metabolic alterations in female mice.

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Pancreatic islet function in a transgenic mouse expressing fluorescent protein

Journal of Endocrinology ◽

10.1677/joe.1.06204 ◽

2005 ◽

Vol 186 (2) ◽

pp. 333-341 ◽

Cited By ~ 14

Author(s):

Daniel Nyqvist ◽

Göran Mattsson ◽

Martin Köhler ◽

Varda Lev-Ram ◽

Arne Andersson ◽

...

Keyword(s):

Pancreatic Islet ◽

Glucose Homeostasis ◽

Fluorescent Protein ◽

Regional Blood Flow ◽

Animal Health ◽

Yellow Fluorescent Protein ◽

Islet Function ◽

Enhanced Yellow Fluorescent Protein ◽

Isolated Pancreatic Islets ◽

Arterial Blood

Pancreatic islet function and glucose homeostasis have been characterized in the transgenic YC-3.0 mouse, which expresses the yellow chameleon 3.0 (YC-3.0) protein under the control of the β-actin and the cytomegalovirus promoters. Fluorescence from the enhanced yellow fluorescent protein (EYFP), one part of the yellow chameleon protein, was used as a reporter of transgene expression. EYFP was expressed in different quantities throughout most cell types, including islet endocrine and stromal cells. No adverse effects of the transgene on animal health, growth or fertility were observed. Likewise, in vivo glucose homeostasis, mean arterial blood pressure and regional blood flow values were normal. Furthermore, the transgenic YC-3.0 mouse had a normal β-cell volume and mass as well as glucose-stimulated insulin release in vitro, compared with the C57BL/6 control mouse. Isolated islets from YC-3.0 animals continuously expressed the transgene and reversed hyperglycemia when transplanted under the renal capsule of alloxan-diabetic nude mice. We conclude that isolated pancreatic islets from YC-3.0 animals implanted into recipients without any EYFP expression, constitute a novel and versatile model for studies of islet engraftment.

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Androgen Suppresses In Vivo and In Vitro LH Pulse Secretion and Neural Kiss1 and Tac2 Gene Expression in Female Mice

Endocrinology ◽

10.1210/endocr/bqaa191 ◽

2020 ◽

Vol 161 (12) ◽

Author(s):

Lourdes A Esparza ◽

Tomohiro Terasaka ◽

Mark A Lawson ◽

Alexander S Kauffman

Keyword(s):

Gene Expression ◽

Pulse Frequency ◽

Normal Male ◽

Steroid Abuse ◽

Female Mice ◽

Reproductive Axis ◽

Lh Pulsatility ◽

Lh Secretion

Abstract Androgens can affect the reproductive axis of both sexes. In healthy women, as in men, elevated exogenous androgens decrease gonad function and lower gonadotropin levels; such circumstances occur with anabolic steroid abuse or in transgender men (genetic XX individuals) taking androgen supplements. The neuroendocrine mechanisms by which endogenous or exogenous androgens regulate gonadotropin release, including aspects of pulsatile luteinizing hormone (LH) secretion, remain unknown. Because animal models are valuable for interrogating neural and pituitary mechanisms, we studied effects of androgens in the normal male physiological range on in vivo LH secretion parameters in female mice and in vitro LH secretion patterns from isolated female pituitaries. We also assessed androgen effects on hypothalamic and gonadotrope gene expression in female mice, which may contribute to altered LH secretion profiles. We used a nonaromatizable androgen, dihydrotestosterone (DHT), to isolate effects occurring specifically via androgen receptor (AR) signaling. Compared with control females, DHT-treated females exhibited markedly reduced in vivo LH pulsatility, with decreases in pulse frequency, amplitude, peak, and basal LH levels. Correlating with reduced LH pulsatility, DHT-treated females also exhibited suppressed arcuate nucleus Kiss1 and Tac2 expression. Separate from these neural effects, we determined in vitro that the female pituitary is directly inhibited by AR signaling, resulting in lower basal LH levels and reduced LH secretory responses to gonadotropin-releasing hormone pulses, along with lower gonadotropin gene expression. Thus, in normal adult females, male levels of androgen acting via AR can strongly inhibit the reproductive axis at both the neural and pituitary levels.

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Interleukin 4 impairs rat pancreatic islet function in vitro by an action different to that of interleukin 1

Cytokine ◽

10.1006/cyto.1995.0036 ◽

1995 ◽

Vol 7 (3) ◽

pp. 296-300 ◽

Cited By ~ 12

Author(s):

Stellan Sandler ◽

Johnny Sternesjö

Keyword(s):

Pancreatic Islet ◽

Interleukin 1 ◽

Interleukin 4 ◽

Islet Function ◽

Rat Pancreatic Islet

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A new scaffold containing small intestinal submucosa and mesenchymal stem cells improves pancreatic islet function and survival in vitro and in vivo

International Journal of Molecular Medicine ◽

10.3892/ijmm.2016.2814 ◽

2016 ◽

Vol 39 (1) ◽

pp. 167-173 ◽

Cited By ~ 8

Author(s):

Dan Wang ◽

Xiaoming Ding ◽

Wujun Xue ◽

Jin Zheng ◽

Xiaohui Tian ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Pancreatic Islet ◽

Small Intestinal Submucosa ◽

Islet Function ◽

Small Intestinal ◽

Intestinal Submucosa

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OR20-02 Maternal Adiponectin Prevents Against Metabolic Dysfunction in Prenatally Androgenized PCOS-Like Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.827 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Anna Benrick ◽

Yanling Wu ◽

Elisabet Stener-Victorin ◽

Ingrid Wernstedt Asterholm

Keyword(s):

Adipose Tissue ◽

Visceral Fat ◽

Polycystic Ovary ◽

Female Offspring ◽

Whole Body ◽

Metabolic Dysfunction ◽

Anogenital Distance ◽

Reproductive Dysfunction ◽

Androgen Exposure ◽

Whole Body Metabolism

Abstract More than 10% of women worldwide are diagnosed with polycystic ovary syndrome (PCOS), causing reproductive and metabolic disease. Hyperandrogenism is the main characteristic and elevated levels of androgens during pregnancy affect placenta function and fetal programming, which leads to reproductive and metabolic dysfunction in the offspring. Adiponectin secreted from adipose tissue improves whole-body metabolism, but its role during pregnancy is under explored. Adiponectin affects placental nutrient transport during pregnancy allowing for speculation that adiponectin can exert endocrine effects on the developing fetus. This study aims to investigate if, in prenatally androgenized (PNA) mice, adiponectin can prevent metabolic and reproductive dysfunction in female offspring. Adiponectin transgenic (APNtg) and wildtype (wt) female mice were mated with wt males, and received dihydrotestosterone or vehicle injections between gestational days 16.5-18.5 to induce a PCOS-like phenotype. The anogenital distance, a marker of in utero androgen exposure, was measured at 22 days of age, estrus cyclicity was recorded at 6 weeks of age, and metabolic measures were performed at 4 months of age. APNtg dams gave birth to significantly smaller offspring, independent of genotype, than wt dams. PNA increased f-insulin in all groups but insulin sensitivity was higher in wt mice from APNtg dams compared to wt mice from wt dams. Insulin resistance correlated with subcutaneous and visceral fat mass. PNA increased visceral fat % and adipocyte size in wt offspring from wt dams while wt and APNtg offspring from APNtg dams were protected against this effect. Visceral adipose tissue gene expression was unaltered in PNA wt offspring, regardless of the dam’s genotype, while APNtg offspring, regardless of PNA, had increased expression of adipogenic genes. Anogenital distance was increased in all PNA wt offspring independent of the dam’s genotype. There was, however, no difference between APNtg-vehicle and APNtg-PNA mice, suggesting that adiponectin overexpression protects against this effect. PNA leads to disrupted estrous cycle and fewer ovulations, but this effect was less pronounced in PNA wt mice from APNtg dams. Our data suggests that elevated maternal adiponectin protects the offspring against PNA induced metabolic dysfunction, and to a lesser extent reproductive dysfunction.

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Mesenchymal Stem Cell Therapy Ameliorates Metabolic Dysfunction and Restores Fertility in a PCOS Mouse Model Through Interleukin-10

10.21203/rs.3.rs-444566/v1 ◽

2021 ◽

Author(s):

Rishi Man Chugh ◽

Hang-soo Park ◽

Abdeljabar El Andaloussi ◽

Amro Elsharoud ◽

Sahar Esfandyari ◽

...

Keyword(s):

Gene Expression ◽

Polycystic Ovary ◽

Therapeutic Option ◽

Interleukin 10 ◽

Reproductive Age ◽

Metabolic Dysfunction ◽

Mesenchymal Stem Cell Therapy ◽

Anti Inflammatory

Abstract Background: Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women. Excessive inflammation and elevated androgen production from ovarian theca cells are key features of PCOS. Human bone marrow mesenchymal stem cells (BM-hMSC) and their secreted factors (secretome) exhibit robust anti-inflammatory capabilities in various biological systems. We evaluated the therapeutic efficacy of BM-hMSC and its secretome in both in vitro and in vivo PCOS models.Methods: For in vitro experiment, we treated conditioned media from BM-hMSC to androgen producing H293R cells, and analyzed androgen producing gene expression. For in vivo experiment, BM-hMSC were implanted into Letrozole (LTZ) induced mouse PCOS model. BM-hMSC effect in androgen producing cells or PCOS model mice was assessed by monitoring cell proliferation (immunohistochemistry), steroidogenic gene expression (quantitative real-time polymerase chain reaction [qRT-PCR] and Western blot, animal tissue assay (H&E staining), and fertility by pup delivery.Results: BM-hMSC significantly downregulate steroidogenic gene expression, curb inflammation, and restore fertility in treated PCOS animals. The anti-inflammatory cytokine interleukin-10 (IL-10) played a key role in mediating the effects of BM-hMSC in our PCOS models. We demonstrated that BM-hMSC treatment was improve in metabolic and reproductive markers in our PCOS model and able to restore fertility. Conclusion: Our study demonstrates for the first time the efficacy of intra-ovarian injection of BM-hMSC or its secretome to treat PCOS-related phenotypes, including both metabolic and reproductive dysfunction. This approach may represent a novel therapeutic option for women with PCOS. Our results suggest that BM-hMSC can reverse PCOS-induced inflammation through IL-10 secretion. BM-hMSC might be a novel and robust therapeutic approach for PCOS treatment.

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