Neuroendocrine Basis for Disrupted Ovarian Cyclicity in Female Mice During Chronic Undernutrition

Endocrinology ◽  
2021 ◽  
Author(s):  
Michael J Kreisman ◽  
Kirollos S Tadrousse ◽  
Richard B McCosh ◽  
Kellie M Breen
Keyword(s):  
Molecular Mechanisms ◽  
Metabolic Stress ◽  
Ovarian Cycle ◽  
Reproductive Capacity ◽  
Lh Surge ◽  
Tightly Coupled ◽  
Estrous Cyclicity ◽  
Chronic Undernutrition ◽  
Multiple Species ◽  
Ovarian Cyclicity

Abstract Chronic undernutrition is a type of metabolic stress that impairs reproduction in multiple species. Although energy balance and female reproductive capacity is recognized as tightly coupled, the neuroendocrine loci and molecular mechanisms that mediate ovarian cycle dysfunction during chronic undernutrition in adult females remain poorly understood. Here, we present a series of studies in which we tested the hypothesis that inhibition of kisspeptin (Kiss1) neurons, which are critical for controlling luteinizing hormone (LH) pulses and the preovulatory LH surge in females, underlies the impairment of the ovarian cycle by undernutrition. We first investigated the effect of chronic undernutrition (70% of unrestricted feed intake) on estrous cyclicity in intact female c57bl6 mice. Undernutrition caused a rapid cessation of ovarian cyclicity during the two-week treatment, suppressing ovarian steroidogenesis and inhibiting ovulation. Using two well-defined estradiol replacement paradigms, we directly tested the hypothesis that undernutrition inhibits Kiss1 neurons in the arcuate nucleus (ARC Kiss1) which are required for LH pulses and in the anteroventral periventricular nucleus (AVPV Kiss1) which are necessary for LH surge secretion. Undernutrition prevented LH pulses and impaired ARC Kiss1 neuronal activation, using c-Fos as a marker, in ovariectomized females subcutaneously implanted with a pellet containing a diestrus-like level of estradiol. In addition, undernutrition completely blocked the estradiol-induced LH surge and diminished Kiss1 mRNA abundance, without decreasing Erα, in micropunches of the AVPV. Collectively, these studies demonstrate that undernutrition disrupts ovarian cyclicity in females via impairment of both ARC Kiss1 control of LH pulses and AVPV Kiss1 induction of the LH surge.

scholarly journals Neuroendocrine Basis for Disrupted Ovarian Cyclicity in Females During Chronic Undernutrition: A Mouse Model

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A546-A546
Author(s):  
Kirollos S Tadrousse ◽  
Richard B McCosh ◽  
Michael J Kreisman ◽  
Kellie M Breen
Keyword(s):  
Molecular Mechanisms ◽  
Control Diet ◽  
Baseline Period ◽  
Ovarian Cycle ◽  
Reproductive Capacity ◽  
Cell Populations ◽  
Feed Restriction ◽  
Lh Surge ◽  
Chronic Undernutrition ◽  
Ovarian Cyclicity

Abstract Chronic undernutrition is a type of metabolic stress that impairs reproduction across species and, in women, is implicated in the development of functional hypothalamic amenorrhea. Although the tight coupling of energy balance to reproductive capacity is recognized in principle, the neuroendocrine loci and molecular mechanisms that mediate ovarian cycle dysfunction during undernutrition remain poorly understood. Ovarian cyclicity is dependent on a population of kisspeptin (Kiss1) neurons in arcuate nucleus (ARCKiss1) for luteinizing hormone (LH) pulses and in the anteroventral periventricular nucleus (AVPVKiss1) for LH surge secretion. Here, we present a series of studies in which we tested the hypothesis that inhibition of both Kiss1 cell populations underlies the impairment of the cycle by undernutrition. During a baseline period, body weight, feed intake, and ovarian cycle stage (via vaginal cytology) were evaluated in female c57bl6 mice. Then, animals were randomly assigned into one of two groups (n=6-8/grp): 1) ad libitum fed controls or 2) feed restricted (70% of feed consumed during the baseline period). Control animals displayed clear and regular cycles throughout the 4-week treatment period. In contrast, feed restriction caused a significant and rapid cessation of ovarian cyclicity (4.8±0.3 vs. 1.5±0.5 estrus cycles/4 weeks; control vs. restricted, p<0.05), causing all females to enter and remain mostly in diestrus. Based on these results, we conducted two experiments to directly test the hypothesis that undernutrition inhibits both modes of LH secretion (and both Kiss1 cell populations) using two well-defined estradiol (E) replacement paradigms. We first evaluated LH pulses in mice that were ovariectomized and implanted subcutaneously with a pellet containing a diestrus level of E (100 ng, OVX+LowE). Following 3 days of feed restriction or control diet (n=3/grp), serial blood samples were collected every 8 min for 88 min. Undernutrition prevented LH pulses and significantly reduced mean LH (5.2±0.6 vs. 0.6±0.2 ng/mL; control vs. restricted, p<0.05). Fixed neural tissue was evaluated by immunohistochemistry to determine whether undernutrition impairs ARCKiss1 neuronal activation, using c-Fos as a marker. The percent of ARCKiss1 neurons expressing cFos was reduced by 90% (p<0.05). We next evaluated the LH surge. After 3 days, control or feed restricted mice were OVX and implanted subcutaneously with a surge-inducing estradiol implant (OVX+HighE, 1 µg, n=3-4/grp). Undernutrition completely blocked the E-induced LH surge (1.9±0.3 vs. 0.2±0.02 ng/mL; control vs. restricted, p<0.05) and diminished Kiss1 mRNA abundance in micropunches of the AVPV (42%, p<0.05). Collectively, these studies clearly show that undernutrition impairs both ARCKiss1 control of LH pulses and AVPVKiss1 induction of the LH surge, via mechanisms that remain to be identified.

Rat mitochondrial ATP synthase ATP5G3: cloning and upregulation in pancreas after chronic ethanol feeding

2001 ◽  
Vol 6 (2) ◽  
pp. 91-98 ◽  
Author(s):  
HA-SHENG LI ◽  
JI-YING ZHANG ◽  
BRYAN S. THOMPSON ◽  
XIAO-YING DENG ◽  
MICHAEL E. FORD ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Metabolic Stress ◽  
Nuclear Gene ◽  
Chronic Ethanol ◽  
Ethanol Ingestion ◽  
Pancreatic Acinar Cells ◽  
Mitochondrial Atp Synthase ◽  
Ethanol Feeding

Individuals with chronic excessive alcohol ingestion are put at the risk of acute and chronic pancreatitis. Underlying molecular mechanisms are unknown. Differential gene expression in the pancreas was profiled using mRNA differential display by comparison between control and ethanol-consuming rats. Male Wistar rats were fed with diets containing 6.7% (vol/vol) ethanol for 4 wk. A cDNA tag that was overexpressed in the pancreas of rats fed ethanol was isolated. A 723-bp cDNA was cloned from a rat pancreatic cDNA library, which encodes a novel rat mitochondrial ATP synthase subunit 9, isoform 3 (ATP5G3), which is homologous to a human ATP5G3 gene. Real-time PCR demonstrated that all three nuclear gene isoforms (ATP5G1, ATP5G2, and ATP5G3) were consistently upregulated in the pancreas of alcohol-consuming rats, parallel with mitochondrial injury. The cellular response to mitochondrial damage and metabolic stress may reflect an adaptive process for mitochondrial repair in pancreatic acinar cells during chronic ethanol ingestion.

scholarly journals The Hypoxia-Inducible Factor Pathway, Prolyl Hydroxylase Domain Protein Inhibitors, and Their Roles in Bone Repair and Regeneration

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Lihong Fan ◽  
Jia Li ◽  
Zefeng Yu ◽  
Xiaoqian Dang ◽  
Kunzheng Wang
Keyword(s):  
Cell Fate ◽  
Bone Repair ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Bone Tumours ◽  
Cell Fate Decisions ◽  
Tightly Coupled ◽  
Hif Pathway ◽  
Prolyl Hydroxylase Domain

Hypoxia-inducible factors (HIFs) are oxygen-dependent transcriptional activators that play crucial roles in angiogenesis, erythropoiesis, energy metabolism, and cell fate decisions. The group of enzymes that can catalyse the hydroxylation reaction of HIF-1 is prolyl hydroxylase domain proteins (PHDs). PHD inhibitors (PHIs) activate the HIF pathway by preventing degradation of HIF-αvia inhibiting PHDs. Osteogenesis and angiogenesis are tightly coupled during bone repair and regeneration. Numerous studies suggest that HIFs and their target gene, vascular endothelial growth factor (VEGF), are critical regulators of angiogenic-osteogenic coupling. In this brief perspective, we review current studies about the HIF pathway and its role in bone repair and regeneration, as well as the cellular and molecular mechanisms involved. Additionally, we briefly discuss the therapeutic manipulation of HIFs and VEGF in bone repair and bone tumours. This review will expand our knowledge of biology of HIFs, PHDs, PHD inhibitors, and bone regeneration, and it may also aid the design of novel therapies for accelerating bone repair and regeneration or inhibiting bone tumours.

scholarly journals Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient mice

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Roman M Stilling ◽  
Gerard M Moloney ◽  
Feargal J Ryan ◽  
Alan E Hoban ◽  
Thomaz FS Bastiaanssen ◽  
...  
Keyword(s):  
Social Interaction ◽  
Social Behaviour ◽  
Rna Splicing ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Gene Expression Response ◽  
Microbe Interactions ◽  
Host Microbe Interactions ◽  
Expression Response ◽  
Multiple Species

Social behaviour is regulated by activity of host-associated microbiota across multiple species. However, the molecular mechanisms mediating this relationship remain elusive. We therefore determined the dynamic, stimulus-dependent transcriptional regulation of germ-free (GF) and GF mice colonised post weaning (exGF) in the amygdala, a brain region critically involved in regulating social interaction. In GF mice the dynamic response seen in controls was attenuated and replaced by a marked increase in expression of splicing factors and alternative exon usage in GF mice upon stimulation, which was even more pronounced in exGF mice. In conclusion, we demonstrate a molecular basis for how the host microbiome is crucial for a normal behavioural response during social interaction. Our data further suggest that social behaviour is correlated with the gene-expression response in the amygdala, established during neurodevelopment as a result of host-microbe interactions. Our findings may help toward understanding neurodevelopmental events leading to social behaviour dysregulation, such as those found in autism spectrum disorders (ASDs).

Follicle dominance and ovarian asymmetry after luteectomy in rhesus monkeys

1982 ◽  
Vol 243 (4) ◽  
pp. E325-E331 ◽  
Author(s):  
A. L. Goodman ◽  
M. J. Koering ◽  
W. E. Nixon ◽  
R. F. Williams ◽  
G. D. Hodgen
Keyword(s):  
Rhesus Monkeys ◽  
Selection Process ◽  
Ovarian Cycle ◽  
Ovarian Activity ◽  
Dominant Follicle ◽  
Lh Surge ◽  
Morphological Asymmetry ◽  
Cynomolgus Macaques ◽  
Follicle Selection ◽  
Midluteal Phase

Previous work demonstrated that asymmetrical ovarian activity accompanies morphological asymmetry during the ovarian cycle in rhesus and cynomolgus macaques. This study was designed to determine whether functional ovarian asymmetry could be used to detect the upcoming dominant follicle (DF) even before it was grossly visible. Revealing a latent DF in this manner would permit a better estimate of the time when dominance of the follicle selected to ovulate is attained. To accomplish this, rhesus monkeys were luteectomized at midluteal phase to synchronize subsequent follicle growth, and 4 or 8 days later either the ipsilateral or contralateral ovary was removed. Unilateral ablation at day 4 (when no DF is grossly apparent) of either ovary produced symmetrical responses: the interval from luteectomy (CLX) to the next luteinizing hormone (LH) surge was extended by about 4 days in both groups (P less than 0.01), i.e., from about 12.5 days to 16.7 +/- 1.6 and 17.0 +/- 1.5 days (mean +/- SE). In contrast, hemiovariectomy at day 8 produced markedly divergent asymmetrical responses. Removal of the ipsilateral ovary 8 days after CLX did not affect the timing of the next LH surge (13.2 +/- 0.6 days), which ordinarily occurs about 12.5 days after CLX alone. However, ablation of the contralateral ovary (bearing the next DF) on day 8 extended the interval from CLX to the next LH surge from about 12.5 to 26.6 +/- 1.3 days. These findings indicate that, during the normal ovarian cycle when menses occurs 2--4 days after luteolysis, the follicle destined to ovulate becomes dominant between the 2nd and 6th day and that attainment of dominance signals the completion of a follicle selection process that begins or resumes promptly after luteolysis.

scholarly journals Gene expression profiling of bovine preovulatory follicles: gonadotropin surge and prostanoid-dependent up-regulation of genes potentially linked to the ovulatory process

Reproduction ◽  
2009 ◽  
Vol 137 (2) ◽  
pp. 297-307 ◽  
Author(s):  
Qinglei Li ◽  
Fermin Jimenez-Krassel ◽  
James J Ireland ◽  
George W Smith
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Lh Surge ◽  
Temporal Regulation ◽  
Cell Compartments ◽  
Follicle Rupture ◽  
Preovulatory Follicles ◽  
Gonadotropin Surge ◽  
Microarray Studies ◽  
Ovulatory Process

The molecular mechanisms of ovulation and luteinization have not been well established, partially due to lack of a comprehensive understanding of functionally significant genes up-regulated in response to an ovulatory stimulus and the signaling pathways involved. In the present study, transcripts increased in bovine preovulatory follicles following a GnRH-induced LH surge were identified using microarray technology. Increased expression of 368 and 878 genes was detected at 12 (368 genes) and 20 h (878 genes) following GnRH injection. The temporal, cell specific and prostanoid-dependent regulation of selected genes (ADAM10,DBI,CD36,MTSS1,TFG, andRABGAP1) identified from microarray studies and related genes (ADAM17andAREG) of potential significance were also investigated. Expression of mRNA forDBIandCD36was simultaneously up-regulated in theca and granulosa cells (GC) following the LH surge, whereas temporal regulation ofADAM10,MTSS1,TFG, andRABGAP1was distinct in the two cell compartments and increased granulosaTFGandRABGAP1mRNA were prostanoid dependent.AREGmRNA was increased in theca and GCs at 12 and 24 h following GnRH injection.ADAM17mRNA was increased in theca, but reduced in GCs 24 h following GnRH injection. The increasedADAM17andAREGmRNA were prostanoid dependent. ADAM10 and ADAM17 protein were increased specifically in the apex but not the base of preovulatory follicles and the increase in ADAM17 was prostanoid dependent. Results reveal novel information on the regulation of preovulatory gene expression and suggest a potential functional role for ADAM10 and ADAM17 proteins in the region of follicle rupture.

Melatonin effects on Fundulus heteroclitus reproduction

2012 ◽  
Vol 24 (6) ◽  
pp. 794 ◽  
Author(s):  
Francesco Lombardo ◽  
Elisabetta Giorgini ◽  
Giorgia Gioacchini ◽  
Francesca Maradonna ◽  
Paolo Ferraris ◽  
...  
Keyword(s):  
Fundulus Heteroclitus ◽  
Molecular Mechanisms ◽  
Electrophoretic Pattern ◽  
Germinal Vesicle ◽  
Marine Species ◽  
Reproductive Capacity ◽  
Hatching Rate ◽  
Embryo Survival ◽  
Positive Role

This study aimed to investigate the effects of two different doses (100 nM (M1) and 1 µM (M2)) of exogenous melatonin on the reproductive capacity of Fundulus heteroclitus. Eight days of melatonin exposure significantly increased the fecundity and embryo survival of F. heteroclitus only in the M2 group compared with the control; the hatching rate was unaffected. Moreover, increases in the local expression of the melatonin receptor (mtnr) gene during follicle maturation were found; however, there were no differences between the experimental groups. Furthermore, in vitro melatonin-treated follicles showed a significantly higher germinal vesicle break down percentage compared with the control, while SDS–PAGE showed no difference in the electrophoretic pattern of the major yolk proteins. Nevertheless, densitometry revealed a greater intensity of the 118-, 95- and 40-kDa components in groups treated with melatonin. Finally, Fourier transform infrared microspectroscopy was applied to classify the different stages of oocyte development (Stages I–II, III and IV) on the basis of their macromolecular composition. The effects induced by melatonin on oogenesis were investigated by comparing vibrational spectra of females exposed to melatonin with those of controls. Changes to the Amide I band, corresponding to an increase in β-structure, were found in oocytes of females exposed to the highest melatonin dose. These results highlight the positive role of melatonin, which is able to enhance the reproductive capacity of F. heteroclitus. Further studies are in progress to better explain the molecular mechanisms by which melatonin treatment affects reproduction in this marine species.

scholarly journals Pausing controls branching between productive and non-productive pathways during initial transcription

2017 ◽  
Author(s):  
David Dulin ◽  
David L. V. Bauer ◽  
Anssi M. Malinen ◽  
Jacob J. W. Bakermans ◽  
Martin Kaller ◽  
...  
Keyword(s):  
Single Molecule ◽  
Transcription Initiation ◽  
Rna Synthesis ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Single Molecule Fret ◽  
Bacterial Rna ◽  
Tightly Coupled ◽  
Relationship Of ◽  
The Relationship

AbstractTranscription in bacteria is controlled by multiple molecular mechanisms that precisely regulate gene expression. Recently, initial RNA synthesis by the bacterial RNA polymerase (RNAP) has been shown to be interrupted by pauses; however, the pausing determinants and the relationship of pausing with productive and abortive RNA synthesis remain poorly understood. Here, we employed single-molecule FRET and biochemical analysis to disentangle the pausing-related pathways of bacterial initial transcription. We present further evidence that region σ3.2 constitutes a barrier after the initial transcribing complex synthesizes a 6-nt RNA (ITC6), halting transcription. We also show that the paused ITC6 state acts as a checkpoint that directs RNAP, in an NTP-dependent manner, to one of three competing pathways: productive transcription, abortive RNA release, or a new unscrunching/scrunching pathway that blocks transcription initiation. Our results show that abortive RNA release and DNA unscrunching are not as tightly coupled as previously thought.

scholarly journals D-Alanine esterification of teichoic acids contributes to Lactobacillus plantarum mediated intestinal peptidase expression and Drosophila growth promotion upon chronic undernutrition

2017 ◽  
Author(s):  
Renata C. Matos ◽  
Hugo Gervais ◽  
Pauline Joncour ◽  
Martin Schwarzer ◽  
Benjamin Gillet ◽  
...  
Keyword(s):  
Cell Wall ◽  
Lactobacillus Plantarum ◽  
Bacterial Cell ◽  
Molecular Mechanisms ◽  
Growth Promotion ◽  
Bacterial Cell Wall ◽  
List Type ◽  
Juvenile Growth ◽  
Teichoic Acids ◽  
Chronic Undernutrition

SummaryThe microbial environment influence animal physiology. However, the underlying molecular mechanisms of such functional interactions are largely undefined. Previously, we showed that upon chronic undernutrition, strains of Lactobacillus plantarum, a dominant commensal partner of Drosophila, promote host juvenile growth and maturation partly via enhanced expression of intestinal peptidases. By screening a transposon insertion library of Lactobacillus plantarum in gnotobiotic Drosophila larvae, we identify a bacterial cell wall modifying machinery encoded by the pbpX2-dltXABCD operon that is critical to enhance host digestive capabilities and promote growth and maturation. Deletion of this operon leads to bacterial cell wall alteration with a complete loss of teichoic acids D-alanylation. We thus conclude that teichoic acids modifications participate in commensal-host interactions and specifically, D-alanine esterification of teichoic acids contributes to optimal L. plantarum mediated intestinal peptidase expression and Drosophila juvenile growth upon chronic undernutrition.Highlights- LpNC8 mutant library screening identifies genes affecting Drosophila growth promotion.- pbpX2-dlt operon is required for D-alanylation of teichoic acids and Drosophila growth.- Deleting the pbpX2-dlt operon alters host intestinal peptidase expression.- Peptidoglycan and pbpX2-dlt dependent signals are required for LpNC8 mediated growth promotion.eTOC blurbAnimals establish interactions with their microbial communities that shape many aspects of their physiology including juvenile growth. However, the underlying molecular mechanisms are largely undefined. Matos et al. reveal that bacterial teichoic acids modifications contribute to host juvenile growth promotion.

scholarly journals Trans-endothelial trafficking of metabolic substrates and its importance in cardio-metabolic disease

2021 ◽  
Author(s):  
Ashton Faulkner
Keyword(s):  
Metabolic Disease ◽  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Molecular Mechanisms ◽  
Metabolic Stress ◽  
Endothelial Barrier ◽  
Metabolic Dysfunction ◽  
Metabolic Substrates ◽  
Disease Understanding ◽  
Novel Therapeutic

The endothelium acts as a gatekeeper, controlling the movement of biomolecules between the circulation and underlying tissues. Although conditions of metabolic stress are traditionally considered as causes of endothelial dysfunction, a principal driver of cardiovascular disease, accumulating evidence suggests that endothelial cells are also active players in maintaining local metabolic homeostasis, in part, through regulating the supply of metabolic substrates, including lipids and glucose, to energy-demanding organs. Therefore, endothelial dysfunction, in terms of altered trans-endothelial trafficking of these substrates, may in fact be an early contributor towards the establishment of metabolic dysfunction and subsequent cardiovascular disease. Understanding the molecular mechanisms that underpin substrate trafficking through the endothelium represents an important area within the vascular and metabolism fields that may offer an opportunity for identifying novel therapeutic targets. This mini-review summarises the emerging mechanisms regulating the trafficking of lipids and glucose through the endothelial barrier and how this may impact on the development of cardio-metabolic disease.

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