Follicle-stimulating hormone (FSH) plays fundamental roles in male and female fertility. FSH is a heterodimeric glycoprotein expressed by gonadotrophs in the anterior pituitary. The hormone-specific FSHβ-subunit is non-covalently associated with the common α-subunit that is also present in the luteinizing hormone (LH), another gonadotrophic hormone secreted by gonadotrophs and thyroid-stimulating hormone (TSH) secreted by thyrotrophs. Several decades of research led to the purification, structural characterization and physiological regulation of FSH in a variety of species including humans. With the advent of molecular tools, availability of immortalized gonadotroph cell lines and genetically modified mouse models, our knowledge on molecular mechanisms of FSH regulation has tremendously expanded. Several key players that regulate FSH synthesis, sorting, secretion and action in gonads and extragonadal tissues have been identified in a physiological setting. Novel post-transcriptional and post-translational regulatory mechanisms have also been identified that provide additional layers of regulation mediating FSH homeostasis. Recombinant human FSH analogs hold promise for a variety of clinical applications, whereas blocking antibodies against FSH may prove efficacious for preventing age-dependent bone loss and adiposity. It is anticipated that several exciting new discoveries uncovering all aspects of FSH biology will soon be forthcoming.
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Nandana Das and T Rajendra Kumar
Siyi Zhu, Hongchen He, Chengfei Gao, Guojing Luo, Ying Xie, Haiming Wang, Li Tian, Xiang Chen, Xijie Yu and Chengqi He
We examined the effects of tumor necrosis factor-α (TNFα) and interleukin-6 (IL6) gene knockout in preserving the bone loss induced by ovariectomy (OVX) and the mechanisms involved in bone metabolism. Twenty female wild-type (WT), TNFα-knockout (TNFα−/−) or IL6-knockout (IL6−/−) mice aged 12 weeks were sham-operated (SHAM) or subjected to OVX and killed after 4 weeks. Bone mass and skeletal microarchitecture were determined using micro-CT. Bone marrow stromal cells (BMSCs) from all three groups (WT, TNFα−/− and IL6−/−) were induced to differentiate into osteoblasts or osteoclasts and treated with 17-β-estradiol. Bone metabolism was assessed by histological analysis, serum analyses and qRT-PCR. OVX successfully induced a high turnover in all mice, but a repair effect was observed in TNFα−/− and IL6−/− mice. The ratio of femoral trabecular bone volume to tissue volume, trabecular number and trabecular thickness were significantly decreased in WT mice subjected to OVX, but increased in TNFα−/− mice (1.62, 1.34, 0.27-fold respectively; P < 0.01) and IL6−/− mice (1.34, 0.80, 0.22-fold respectively; P < 0.01). Furthermore, we observed a 29.6% increase in the trabecular number in TNFα−/− mice when compared to the IL6−/− mice. Both, TNFα−/− and IL6−/− BMSCs exhibited decreased numbers of TRAP-positive cells and an increase in ALP-positive cells, with or without E2 treatment (P < 0.05). While the knockout of TNFα or IL6 significantly upregulated mRNA expressions of osteoblast-related genes (Runx2 and Col1a1) and downregulated osteoclast-related mRNA for TRAP, MMP9 and CTSK in vivo and in vitro, TNFα knockout appeared to have roles beyond IL6 knockout in upregulating Col1a1 mRNA expression and downregulating mRNA expressions of WNT-related genes (DKK1 and Sost) and TNF-related activation-induced genes (TRAF6). TNFα seemed to be more potentially invasive in inhibiting bone formation and enhancing TRAF6-mediated osteoclastogenesis than IL6, implying that the regulatory mechanisms of TNFα and IL6 in bone metabolism may be different.
Carlos Gaspar, Jonás I Silva-Marrero, María C Salgado, Isabel V Baanante and Isidoro Metón
Glutamate dehydrogenase (Gdh) plays a central role in ammonia detoxification by catalysing reversible oxidative deamination of l-glutamate into α-ketoglutarate using NAD+ or NADP+ as cofactor. To gain insight into transcriptional regulation of glud, the gene that codes for Gdh, we isolated and characterised the 5′ flanking region of glud from gilthead sea bream (Sparus aurata). In addition, tissue distribution, the effect of starvation as well as short- and long-term refeeding on Gdh mRNA levels in the liver of S. aurata were also addressed. 5′-Deletion analysis of glud promoter in transiently transfected HepG2 cells, electrophoretic mobility shift assays, chromatin immunoprecipitation (ChIP) and site-directed mutagenesis allowed us to identify upstream stimulatory factor 2 (Usf2) as a novel factor involved in the transcriptional regulation of glud. Analysis of tissue distribution of Gdh and Usf2 mRNA levels by reverse transcriptase-coupled quantitative real-time PCR (RT-qPCR) showed that Gdh is mainly expressed in the liver of S. aurata, while Usf2 displayed ubiquitous distribution. RT-qPCR and ChIP assays revealed that long-term starvation down-regulated the hepatic expression of Gdh and Usf2 to similar levels and reduced Usf2 binding to glud promoter, while refeeding resulted in a slow but gradual restoration of both Gdh and Usf2 mRNA abundance. Herein, we demonstrate that Usf2 transactivates S. aurata glud by binding to an E-box located in the proximal region of glud promoter. In addition, our findings provide evidence for a new regulatory mechanism involving Usf2 as a key factor in the nutritional regulation of glud transcription in the fish liver.
Joram D Mul
Acute or chronic exposure to stress can increase the risk to develop major depressive disorder, a severe, recurrent and common psychiatric condition. Depression places an enormous social and financial burden on modern society. Although many depressed patients are treated with antidepressants, their efficacy is only modest, underscoring the necessity to develop clinically effective pharmaceutical or behavioral treatments. Exercise training produces beneficial effects on stress-related mental disorders, indicative of clinical potential. The pro-resilient and antidepressant effects of exercise training have been documented for several decades. Nonetheless, the underlying molecular mechanisms and the brain circuitries involved remain poorly understood. Preclinical investigations using voluntary wheel running, a frequently used rodent model that mimics aspects of human exercise training, have started to shed light on the molecular adaptations, signaling pathways and brain nuclei underlying the beneficial effects of exercise training on stress-related behavior. In this review, I highlight several neurotransmitter systems that are putative mediators of the beneficial effects of exercise training on mental health, and review recent rodent studies that utilized voluntary wheel running to promote our understanding of exercise training-induced central adaptations. Advancements in our mechanistic understanding of how exercise training induces beneficial neuronal adaptations will provide a framework for the development of new strategies to treat stress-associated mental illnesses.
Sang R Lee, Mi-Young Park, Hyun Yang, Geun-Shik Lee, Beum-Soo An, Bae-kuen Park, Eui-Bae Jeung and Eui-Ju Hong
Androgens act in concert with vitamin D to influence reabsorption of calcium. However, it is unclear whether androgens directly regulate vitamin D homeostasis or control other cellular events that are related to vitamin D metabolism. To examine whether the expression of vitamin D-related genes in mouse kidney is driven by androgens or androgen-dependent effects, the androgen receptor and other sex steroid receptors were monitored in orchidectomized mice treated with 5α-dihydrotestosterone (DHT). Our results revealed that exposing orchidectomized mice to DHT inhibited the expression of progesterone receptor (Pgr) with or without estrogen receptor α expression, the latter was confirmed by ER-positive (MCF7 and T47D) or -negative (PCT) cells analysis. The loss of Pgr in turn decreased the expression of renal 24-hydroxylase via transcriptional regulation because Cyp24a1 gene has a progesterone receptor-binding site on promoter. When male kidneys preferentially hydroxylate 25-hydroxyvitamin D3 using 24-hydroxylase rather than 25-hydroxyvitamin D3-1-alpha hydroxylase, DHT suppressed the Pgr-mediated 24-hydroxylase expression, and it is important to note that DHT increased the blood 25-hydroxyvitamin D3 levels. These findings uncover an important link between androgens and vitamin D homeostasis and suggest that therapeutic modulation of Pgr may be used to treat vitamin D deficiency and related disorders.
Matthew Stagl, Mary Bozsik, Christopher Karow, David Wertz, Ian Kloehn, Savin Pillai, Paul J Gasser, Marieke R Gilmartin and Jennifer A Evans
Glucocorticoid production is gated at the molecular level by the circadian clock in the adrenal gland. Stress influences daily rhythms in behavior and physiology, but it remains unclear how stress affects the function of the adrenal clock itself. Here, we examine the influence of stress on adrenal clock function by tracking PERIOD2::LUCIFERASE (PER2::LUC) rhythms in vitro. Relative to non-stressed controls, adrenals from stressed mice displayed marked changes in PER2::LUC rhythms. Interestingly, the effect of stress on adrenal rhythms varied by sex and the type of stress experienced in vivo. To investigate the basis of sex differences in the adrenal response to stress, we next stimulated male and female adrenals in vitro with adrenocorticotropic hormone (ACTH). ACTH shifted phase and increased amplitude of adrenal PER2::LUC rhythms. Both phase and amplitude responses were larger in female adrenals than in male adrenals, an observation consistent with previously described sex differences in the physiological response to stress. Lastly, we reversed the sex difference in adrenal clock function using stress and sex hormone manipulations to test its role in driving adrenal responses to ACTH. We find that adrenal responsiveness to ACTH is inversely proportional to the amplitude of adrenal PER2::LUC rhythms. This suggests that larger ACTH responses from female adrenals may be driven by their lower amplitude molecular rhythms. Collectively, these results indicate a reciprocal relationship between stress and the adrenal clock, with stress influencing adrenal clock function and the state of the adrenal clock gating the response to stress in a sexually dimorphic manner.
Louise Ruby Høj Illum, Stine Thorhauge Bak, Sten Lund and Anders Lade Nielsen
The global rise in metabolic diseases can be attributed to a complex interplay between biology, behavior and environmental factors. This article reviews the current literature concerning DNA methylation-based epigenetic inheritance (intergenerational and transgenerational) of metabolic diseases through the male germ line. Included are a presentation of the basic principles for DNA methylation in developmental programming, and a description of windows of susceptibility for the inheritance of environmentally induced aberrations in DNA methylation and their associated metabolic disease phenotypes. To this end, escapees, genomic regions with the intrinsic potential to transmit acquired paternal epigenetic information across generations by escaping the extensive programmed DNA demethylation that occurs during gametogenesis and in the zygote, are described. The ongoing descriptive and functional examinations of DNA methylation in the relevant biological samples, in conjugation with analyses of non-coding RNA and histone modifications, hold promise for improved delineation of the effect size and mechanistic background for epigenetic inheritance of metabolic diseases.
Yachao Zhang, Jieqiong Yang, Shijian Lv, Dong-Qin Zhao, Zi-Jiang Chen, Wei-Ping Li and Cong Zhang
Preeclampsia (PE) is a pregnancy-induced disorder characterized by hypertension and proteinuria after 20 weeks of gestation, affecting 5–7% of pregnancies worldwide. So far, the etiology of PE remains poorly understood. Abnormal decidualization is thought to contribute to the development of PE. SP1 belongs to the Sp/KLF superfamily and can recruit P300 to regulate the transcription of several genes. SP1 is also very important for decidualization as it enhances the expression of tissue factor. In this study, we investigated the expression of SP1 and P300 in deciduae and their relationship with PE. A total of 42 decidua samples were collected, of which 21 were from normal pregnant (NP) and 21 from severe PE. SP1 and P300 expression in deciduae and the levels of SP1 and P300 in cultured human endometrial stromal cells (hESCs) and primary hESCs during decidualization were determined. To further investigate the role of SP1 and P300 in human decidualization, RNA interference was used to silence SP1 and P300 in hESCs and primary hESCs. The following results were obtained. We found that the expressions of SP1 and P300 were reduced in decidual tissues with PE compared to those from NP. In the in vitro model of induction of decidualization, we found an increase in both SP1 and P300 levels. Silencing of SP1 and P300 resulted in abnormal decidualization and a significant reduction of decidualization markers such as insulin-like growth factor-binding protein1 and prolactin. Furthermore, the expression of vascular endothelial growth factor was also decreased upon SP1 and P300 silencing. Similar results were observed in primary hESCs. Our results suggest that SP1 and P300 play an important role during decidualization. Dysfunction of SP1 and P300 leads to impaired decidualization and might contribute to PE.
Marc Simard, Caroline Underhill and Geoffrey L Hammond
Corticosteroid-binding globulin (CBG) is a plasma carrier of glucocorticoids. Human and rat CBGs have six N-glycosylation sites. Glycosylation of human CBG influences its steroid-binding activity, and there are N-glycosylation sites in the reactive center loops (RCLs) of human and rat CBGs. Proteolysis of the RCL of human CBG causes a structural change that disrupts steroid binding. We now show that mutations of conserved N-glycosylation sites at N238 in human CBG and N230 in rat CBG disrupt steroid binding. Inhibiting glycosylation by tunicamycin also markedly reduced human and rat CBG steroid-binding activities. Deglycosylation of fully glycosylated human CBG or human CBG with only one N-glycan at N238 with Endo H-reduced steroid-binding affinity, while PNGase F-mediated deglycosylation does not, indicating that steroid binding is preserved by deamidation of N238 when its N-glycan is removed. When expressed in N-acetylglucosaminyltransferase-I-deficient Lec1 cells, human and rat CBGs, and a human CBG mutant with only one glycosylation site at N238, have higher (2–4 fold) steroid-binding affinities than when produced by sialylation-deficient Lec2 cells or glycosylation-competent CHO-S cells. Thus, the presence and composition of an N-glycan in this conserved position both appear to influence the steroid binding of CBG. We also demonstrate that neutrophil elastase cleaves the RCL of human CBG and reduces its steroid-binding capacity more efficiently than does chymotrypsin or the Pseudomonas aeruginosa protease LasB. Moreover, while glycosylation of N347 in the RCL limits these activities, N-glycans at other sites also appear to protect CBG from neutrophil elastase or chymotrypsin.
Heather C Denroche and C Bruce Verchere
Islet amyloid polypeptide (IAPP), the main component of islet amyloid in type 2 diabetes and islet transplants, is now recognized as a contributor to beta cell dysfunction. Increasingly, evidence warrants its investigation in type 1 diabetes owing to both its immunomodulatory and metabolic actions. Autoreactive T cells to IAPP-derived epitopes have been described in humans, suggesting that IAPP is an islet autoantigen in type 1 diabetes. In addition, although aggregates of IAPP have not been implicated in type 1 diabetes, they are potent pro-inflammatory stimuli to innate immune cells, and thus, could influence autoimmunity. IAPP aggregates also occur rapidly in transplanted islets and likely contribute to islet transplant failure in type 1 diabetes through sterile inflammation. In addition, since type 1 diabetes is a disease of both insulin and IAPP deficiency, clinical trials have examined the potential benefits of IAPP replacement in type 1 diabetes with the injectable IAPP analogue, pramlintide. Pramlintide limits postprandial hyperglycemia by delaying gastric emptying and suppressing hyperglucagonemia, underlining the possible role of IAPP in postprandial glucose metabolism. Here, we review IAPP in the context of type 1 diabetes: from its potential involvement in type 1 diabetes pathogenesis, through its role in glucose metabolism and use of IAPP analogues as therapeutics, to its potential role in clinical islet transplant failure and considerations in this regard for future beta cell replacement strategies.