Pharmacological Inhibition of Inositol Hexakisphosphate Kinase 1 Protects Mice against Obesity-Induced Bone Loss.

Obesity and type II diabetes mellitus (T2DM) are prominent risk factors for secondary osteoporosis due to the negative impacts of hyperglycemia and excessive body fat on bone metabolism. While the armamentarium of anti-diabetic drugs is expanding, their negative or unknown impacts on bone metabolism limits effectiveness. The inactivation of inositol hexakisphosphate kinase 1 (IP6K1) protects mice from high-fat-diet (HFD)-induced obesity (DIO) and insulin resistance by enhancing thermogenic energy expenditure, but the role of this kinase and the consequences of its inhibition on bone metabolism are unknown.

Multiple Lesions Contribute to Infertility in Males Lacking Autoimmune Regulator.

Male factors, including those of autoimmune origin, contribute to approximately 50% of infertility cases in humans. However, the mechanisms underlying autoimmune male infertility are poorly understood. Deficiency in autoimmune regulator (AIRE) impairs central immune tolerance because of diminished expression of self-antigens in the thymus.

Mice lacking uterine enhancer of zeste homolog 2 have transcriptomic changes associated with uterine epithelial proliferation.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that suppresses gene expression. Previously, we developed a conditional null model where EZH2 is knocked out in uterus. Deletion of uterine EZH2 increased proliferation of luminal and glandular epithelial cells.

The histone methyltransferase EZH2 is required for normal uterine development and function in mice†.

Enhancer of zeste homolog 2 (EZH2) is a rate-limiting catalytic subunit of a histone methyltransferase, polycomb repressive complex, which silences gene activity through the repressive histone mark H3K27me3. EZH2 is critical for epigenetic effects of early estrogen treatment, and may be involved in uterine development and pathologies. We investigated EZH2 expression, regulation, and its role in uterine development/function.

Mice lacking membrane estrogen receptor 1 are protected from reproductive pathologies resulting from developmental estrogen exposure†.

Both membrane and nuclear fractions of estrogen receptor 1 (ESR1) mediate 17β-estradiol (E2) actions. Mice expressing nuclear (n)ESR1 but lacking membrane (m)ESR1 (nuclear-only estrogen receptor 1 [NOER] mice) show reduced E2 responsivity and reproductive abnormalities culminating in adult male and female infertility. Using this model, we investigated whether reproductive pathologies caused by the synthetic estrogen diethylstilbestrol (DES) are mitigated by mESR1 ablation.

Membrane estrogen receptor 1 is required for normal reproduction in male and female mice.

Steroid hormones, acting through their cognate nuclear receptors, are critical for many reproductive and non-reproductive functions. Over the past two decades, it has become increasingly clear that in addition to cytoplasmic/nuclear steroid receptors that alter gene transcription when liganded, a small fraction of cellular steroid receptors are localized to the cell membranes, where they mediate rapid steroid hormone effects. 17β-Estradiol (E2), a key steroid hormone for both male and female reproduction, acts predominately through its main receptor, estrogen receptor 1 (ESR1).

Estrogens in Male Physiology.

Estrogens have historically been associated with female reproduction, but work over the last two decades established that estrogens and their main nuclear receptors (ESR1 and ESR2) and G protein-coupled estrogen receptor (GPER) also regulate male reproductive and nonreproductive organs. 17β-Estradiol (E2) is measureable in blood of men and males of other species, but in rete testis fluids, E2 reaches concentrations normally found only in females and in some species nanomolar concentrations of estrone sulfate are found in semen. Aromatase, which converts androgens to estrogens, is expressed in Leydig cells, seminiferous epithelium, and other male organs.

Another piece of the meiosis puzzle.

Meiosis, the process by which the ovary and testis produce haploid gametes from initially diploid cells, is essential for sexual reproduction in mammals. This process, initially described in the late 19 and early 20 century using model organisms such as sea urchins, worms and fruit flies, continues to attract extensive interest from reproductive biologists due to its centrality in gametogenesis. The simple observational techniques used to initially describe meiosis have in more recent times given way to mechanistic molecular, cellular and biochemical approaches.

Membrane-Localized Estrogen Receptor 1 Is Required for Normal Male Reproductive Development and Function in Mice.

Estrogen receptor 1 (ESR1) mediates major reproductive functions of 17β-estradiol (E2). Male Esr1 knockout (Esr1KO) mice are infertile due to efferent ductule and epididymal abnormalities. The majority of ESR1 is nuclear/cytoplasmic; however, a small fraction is palmitoylated at cysteine 451 in mice and localized to cell membranes, in which it mediates rapid E2 actions.

Maximal Dexamethasone Inhibition of Luminal Epithelial Proliferation Involves Progesterone Receptor (PR)- and Non-PR-Mediated Mechanisms in Neonatal Mouse Uterus.

Progesterone (P4) and the synthetic glucocorticoid dexamethasone (Dex) inhibit luminal epithelial (LE) proliferation in neonatal mouse uteri. This study determined the roles of progesterone receptor and estrogen receptor 1 (PR and ESR1, respectively) in P4- and Dex-induced inhibition of LE proliferation using PR knockout (PRKO) and Esr1 knockout (Esr1KO) mice. Wild-type (WT), heterozygous, and homozygous PRKO female pups were injected with vehicle, P4 (40 μg/g body weight), or Dex (4 or 40 μg/g body weight) on Postnatal Day 5, then 24 h later immunostained for markers of cell proliferation.

How to make a human germ cell.

How the primordial germ cell (PGC) lineage, which eventually gives rise to spermatozoa in males and oocytes in females, is established in the developing mammalian embryo has been a critical topic in both developmental and reproductive biology for many years. There have been significant breakthroughs over the past two decades in establishing both the source of PGCs and the factors that regulate the specification of this lineage in mice, [1] but our understanding of the factors that control PGC development in the human is rudimentary. The SRY-related HMG-box (SOX) family of transcription factors consists of 20 genes in humans and mice that are involved in the maintenance of pluripotency, male sexual development, and other processes.

Plasticity of spermatogonial stem cells.

There have been significant breakthroughs over the past decade in the development and use of pluripotent stem cells as a potential source of cells for applications in regenerative medicine. It is likely that this methodology will begin to play an important role in human clinical medicine in the years to come. This review describes the plasticity of one type of pluripotent cell, spermatogonial stem cells (SSCs), and their potential therapeutic applications in regenerative medicine and male infertility.

Neonatal uterine and vaginal cell proliferation and adenogenesis are independent of estrogen receptor 1 (ESR1) in the mouse.

Neonatal uterus and vagina express estrogen receptor 1 (ESR1) and respond mitogenically to exogenous estrogens. However, neonatal ovariectomy does not inhibit preweaning uterine cell proliferation, indicating that this process is estrogen independent. Extensive literature suggests that ESR1 can be activated by growth factors in a ligand-independent manner and drive uterine cell proliferation.

Bisphenol A regulation of testicular endocrine function in male rats is affected by diet.

There is concern that early-life exposure to bisphenol A (BPA) may alter developmental programming and predispose individuals to obesity and reproductive anomalies. The present study was designed to determine if a high fat diet at sexual maturation moderates testicular toxicity occasioned by exposure to BPA during reproductive development. Therefore, male rats were exposed to BPA by maternal gavage (0, 2.

Aflatoxin B1 disrupts the androgen biosynthetic pathway in rat Leydig cells.

The present study investigated if Aflatoxin B1 (AFB1), a potent and naturally occurring mycotoxin, interferes with the steroidogenic pathway in rat Leydig cells. Testicular Leydig cells are the predominant source of the male sex steroid hormone testosterone (T) that maintains the male phenotype and support fertility. Leydig cells, isolated from 35-day-old male Long-Evans rats (Rattus norvegicus), were incubated with AFB1 at 0, 0.

Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms.

Traumatic brain injury (TBI) is an important and costly medical problem for which no clinically proven treatment currently exists. Studies in rodents and humans have shown beneficial effects of progesterone (P4) on both mortality and functional outcomes following TBI. Neuroprotective effects of P4 in TBI likely involve the classical nuclear progesterone receptors (Pgr) that are widely distributed in both glial cells and neurons of the brain.

The industrial chemical bisphenol A (BPA) interferes with proliferative activity and development of steroidogenic capacity in rat Leydig cells.

The presence of bisphenol A (BPA) in consumer products has raised concerns about potential adverse effects on reproductive health. Testicular Leydig cells are the predominant source of the male sex steroid hormone testosterone, which supports the male phenotype. The present report describes the effects of developmental exposure of male rats to BPA by gavage of pregnant and lactating Long-Evans dams at 2.

Regulation of adiponectin secretion by soy isoflavones has implication for endocrine function of the testis.

Testicular Leydig cells are the predominant source of the male sex steroid hormone testosterone (T), which is required to maintain male fertility. There is now growing evidence that environmental stressors, including chemicals present in food, air and water, may affect energy balance. A relationship between energy balance and reproductive capacity has been proposed for a long time.