Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome.

ABSTRACT: Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csb(m/m)/Xpa(-/-) mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m)/Xpa(-/-) mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m)/Xpa(-/-) and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.

SUBMITTER: van der Pluijm I

PROVIDER: S-EPMC1698505 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Neuron-specific Mafb knockout causes growth retardation accompanied by an impaired growth hormone/insulin-like growth factor I axis.

Project description:Mammalian postnatal growth is regulated primarily by the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. MafB is a basic leucine zipper (bZip) transcription factor that has pleiotropic functions. Although MafB plays a critical role in fetal brain development, such as in guidance for hindbrain segmentation, its postnatal role in neurons remains to be elucidated. To investigate this, we used neuron-specific Mafb conditional knockout (cKO) mice. In addition to an approximately 50% neonatal viability, the Mafb cKO mice exhibited growth retardation without apparent signs of low energy intake. Notably, serum IGF-I levels of these mice in the postnatal stage were lower than those of control mice. They seemed to have a neuroendocrine dysregulation, as shown by the upregulation of serum GH levels in the resting state and an inconsistent secretory response of GH upon administration of growth hormone-releasing hormone. These findings reveal that neuronal MafB plays an important role in postnatal development regulated by the GH/IGF-I axis.

| S-EPMC6842794 | biostudies-literature

Growth Hormone/Insulin Growth Factor Axis in Sex Steroid Associated Disorders and Related Cancers.

Project description:To date, almost all solid malignancies have implicated insulin-like growth factor (IGF) signalling as a driver of tumour growth. However, the remarkable level of crosstalk between sex hormones, the IGF-1 receptor (IGF-1R) and its ligands IGF-1 and 2 in endocrine driven cancers is incompletely understood. Similar to the sex steroids, IGF signalling is essential in normal development as well as growth and tissue homoeostasis, and undergoes a steady decline with advancing age and increasing visceral adiposity. Interestingly, IGF-1 has been found to play a compensatory role for both estrogen receptor (ER) and androgen receptor (AR) by augmenting hormonal responses in the absence of, or where low levels of ligand are present. Furthermore, experimental, and epidemiological evidence supports a role for dysregulated IGF signalling in breast and prostate cancers. Insulin-like growth factor binding protein (IGFBP) molecules can regulate the bioavailability of IGF-1 and are frequently expressed in these hormonally regulated tissues. The link between age-related disease and the role of IGF-1 in the process of ageing and longevity has gained much attention over the last few decades, spurring the development of numerous IGF targeted therapies that have, to date, failed to deliver on their therapeutic potential. This review will provide an overview of the sexually dimorphic nature of IGF signalling in humans and how this is impacted by the reduction in sex steroids in mid-life. It will also explore the latest links with metabolic syndromes, hormonal imbalances associated with ageing and targeting of IGF signalling in endocrine-related tumour growth with an emphasis on post-menopausal breast cancer and the impact of the steroidal milieu.

| S-EPMC8012538 | biostudies-literature

Modulation of growth hormone receptor-insulin-like growth factor 1 axis by dietary protein in young ruminants.

Project description:A reduced protein intake causes a decrease in insulin-like growth factor 1 (IGF1) concentrations and modulates Ca homoeostasis in young goats. IGF1 is synthesised by the liver in response to stimulation by growth hormone (GH). Due to rumino-hepatic circulation of urea, ruminants are suitable for investigating the effects of protein reduction despite sufficient energy intake. The present study aimed to investigate the impact of a protein-reduced diet on the expression of components of the somatotropic axis. Male young goats were divided into two feeding groups receiving either a control diet (20 % crude protein (CP)) or a reduced-protein diet (9 % CP). Blood concentrations of IGF1 and GH were measured, and a 24-h GH secretion profile was compiled. Moreover, ionised Ca and insulin concentrations as well as mRNA and protein expression levels of hepatic proteins involved in GH signalling were quantified. Due to the protein-reduced diet, concentrations of ionised Ca, insulin and IGF1 decreased significantly, whereas GH concentrations remained unchanged. Expression levels of the hepatic GH receptor (GHR) decreased during protein reduction. GHR expression was down-regulated due to diminished insulin concentrations as both parameters were positively correlated. Insulin itself might be reduced due to reduced blood Ca levels that are involved in insulin release. The protein-reduced diet had an impact on the expression of components of the somatotropic axis as a disruption of the GH-IGF1 axis brought about by diminished GHR expression was shown in response to a protein-reduced diet.

| S-EPMC7025161 | biostudies-literature

Genetic Defects in the Growth Hormone-IGF-I Axis Causing Growth Hormone Insensitivity and Impaired Linear Growth.

Project description:Human genetic defects in the growth hormone (GH)-IGF-I axis affecting the IGF system present with growth failure as their principal clinical feature. This is usually associated with GH insensitivity (GHI) presenting in childhood as severe or mild short stature. Dysmorphic features and metabolic abnormalities may also be present. The field of GHI due to mutations affecting GH action has evolved rapidly since the first description of the extreme phenotype related to homozygous GH receptor (GHR) mutations in 1966. A continuum of genetic, phenotypic, and biochemical abnormalities can be defined associated with clinically relevant defects in linear growth. The mechanisms of the GH-IGF-I axis in the regulation of normal human growth is discussed followed by descriptions of mutations in GHR, STAT5B, IGF-I, IGFALS, IGF1R, and GH1 defects causing bio-inactive GH or anti-GH antibodies. These GH-IGF-I axis defects are associated with a range of clinical, and hormonal characteristics. An up-dated approach to the clinical assessment of the patient with GHI focusing on investigation of the GH-IGF-I axis and relevant molecular studies contributing to the identification of causative genetic defects is also discussed.

| S-EPMC3356141 | biostudies-literature

Nutritional supplementation of breeding hens may promote embryonic development through the growth hormone-insulin like growth factor axis.

Project description:The late stage of embryo development is a crucial period of metabolic changes, with rapid organ development requiring a substantial supply of nutrients. During this phase, maternal nutritional levels play a vital role in the growth, development, and metabolism of the offspring. In this study, we added 2 doses of β-carotene (βc) (120 mg/kg and 240 mg/kg) to the daily diet of Hailan Brown laying hens to investigate the impact of maternal nutritional enrichment on embryo development. Maternal nutrition supplementation significantly increased the expression of chicken embryo liver index, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and hepatocyte growth factor (HGF) in serum. At the same time, the expression of GH/growth hormone receptor (GHR), IGF-1 mRNA, and Proliferating Cell Nuclear Antigen (PCNA) protein in the liver was upregulated, indicating that maternal nutrition intervention may promote chicken embryo liver development through the GH-IGF-1 axis. Transcriptome sequencing results showed that differential genes in liver after maternal nutritional supplementation with β-carotene were enriched in pathways related to cell proliferation and metabolism. Consequently, we postulated that maternal β-carotene supplementation might operate via the GH-IGF-1 axis to regulate the expression of genes involved in growth and development, thereby promoting liver development. These results contribute to formulating more effective poultry feeding strategies to promote offspring growth and development.

| S-EPMC11246051 | biostudies-literature

Association between Growth Hormone-Insulin-Like Growth Factor-1 Axis Gene Polymorphisms and Short Stature in Chinese Children.

Project description:ObjectiveThis study was designed to analyze the association between the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis gene polymorphisms and short stature in Chinese children.Methods181 growth hormone deficiency (GHD) patients and 206 normal stature controls were enrolled to attend this study. Five single-nucleotide polymorphisms in the GH receptor (GHR) and 5 SNPs within the GH-signaling pathway were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry. We conducted an association study between these SNPs and the risk of developing short stature. Linkage disequilibrium analysis was performed using Haploview software and the associations of the SNPs frequencies with short stature were analyzed using X2 tests.ResultsNo significant difference was found in gender, weight, height, and BMI between the GHD and control groups, except that the age of GHD group was older than the control one. Allele and genotype frequencies were consistent with those expected from Hardy-Weinberg equilibrium. Compared with the controls, heterozygous genotype frequencies (CT) of rs12515480 and rs6873545 of GHR gene were significantly lower. Genotype frequencies of the other 8 SNPs did not show significant difference between these two groups. Considering a dominant model, an OR < 1 was observed for genotypes rs12515480 (OR = 0.532, P = 0.019) and rs6873545 (OR = 0.587, P = 0.017).ConclusionsThe heterozygous genotypes of rs12515480 and rs6873545 of GHR gene were associated with decreased risk of GHD in Chinese children.

| S-EPMC5857343 | biostudies-literature

SIRT1 regulates adaptive response of the growth hormone--insulin-like growth factor-I axis under fasting conditions in liver.

Project description:Adaptation under fasting conditions is critical for survival in animals. Sirtuin 1 (SIRT1), a protein deacetylase, plays an essential role in adaptive metabolic and endocrine responses under fasting conditions by modifying the acetylation status of various proteins. Fasting induces growth hormone (GH) resistance in the liver, leading to decreased serum insulin-like growth factor-I (IGF-I) levels as an endocrine adaptation for malnutrition; however, the underlying mechanisms of this action remain to be fully elucidated. Here we report that in vivo knockdown of SIRT1 in the liver restored the fasting-induced decrease in serum IGF-I levels and enhanced the GH-dependent increase in IGF-I levels, indicating that SIRT1 negatively regulates GH-dependent IGF-I production in the liver. In vitro analysis using hepatocytes demonstrated that SIRT1 suppresses GH-dependent IGF-I expression, accompanied by decreased tyrosine phosphorylation on signal transducer and activator of transcription (STAT) 5. GST pull-down assays revealed that SIRT1 interacts directly with STAT5. When the lysine residues adjacent to the SH2 domain of STAT5 were mutated, STAT5 acetylation decreased concomitant with a decrease in its transcriptional activity. Knockdown of SIRT1 enhanced the acetylation and GH-induced tyrosine phosphorylation of STAT5, as well as the GH-induced interaction of the GH receptor with STAT5. These data indicate that SIRT1 negatively regulates GH-induced STAT5 phosphorylation and IGF-I production via deacetylation of STAT5 in the liver. In addition, our findings explain the underlying mechanisms of GH resistance under fasting conditions, which is a known element of endocrine adaptation during fasting.

| S-EPMC3773795 | biostudies-literature

Association Between the Growth Hormone/Insulin-Like Growth Factor-1 Axis and Muscle Density in Children and Adolescents of Short Stature.

Project description:ObjectiveTo evaluate the association between the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis and muscle density in children and adolescents of short stature.MethodsParticipants were children and adolescents of short stature hospitalized in the Affiliated Hospital of Jining Medical University between January 2020 and June 2021. All participants had CT scan images available. We performed an analysis of the images to calculate the muscle density or skeletal muscle attenuation (SMA), skeletal muscle index (SMI), and fat mass index (FMI). Bioelectrical impedance analysis (BIA) was used to ensure that chest CT is a credible way of evaluating body composition.ResultsA total of 297 subjects were included with the mean age of 10.00 ± 3.42 years, mean height standard deviation score (SDS) of -2.51 ± 0.53, and mean IGF-1 SDS of -0.60 ± 1.07. The areas of muscle and fat tissues at the fourth thoracic vertebra level in the CT images showed strong correlation with the total weights of the participants (R2 = 0.884 and 0.897, respectively). The peak of GH was negatively associated with FMI (r = - 0.323, P <.01) and IGF-1 SDS was positively associated with SMI (r = 0.303, P <.01). Both the peak GH and IGF-1 SDS were positively associated with SMA (r = 0.244, P <.01 and r = 0.165, P <.05, respectively). Multiple stepwise linear regression analysis demonstrated that the GH peak was the predictor of FMI (β = - 0.210, P < .01), the IGF-1 SDS was the predictor of SMI (β = 0.224, P < .01), and both the peak GH and IGF-1 SDS were predictors of SMA (β = 0.180, P < .01 and β = 0.222, P < .01).ConclusionsA chest CT scan is a credible method of evaluating body composition in children and adolescents of short stature. In these patients, peak GH and IGF-1 SDS are independent predictors of muscle density and the GF/IGF-1 axis may regulate body composition through complex mechanisms.

| S-EPMC9238351 | biostudies-literature

Skeletal effects of growth hormone and insulin-like growth factor-I therapy.

Project description:The growth hormone/insulin-like growth factor (GH/IGF) axis is critically important for the regulation of bone formation, and deficiencies in this system have been shown to contribute to the development of osteoporosis and other diseases of low bone mass. The GH/IGF axis is regulated by a complex set of hormonal and local factors which can act to regulate this system at the level of the ligands, receptors, IGF binding proteins (IGFBPs), or IGFBP proteases. A combination of in vitro studies, transgenic animal models, and clinical human investigations has provided ample evidence of the importance of the endocrine and local actions of both GH and IGF-I, the two major components of the GH/IGF axis, in skeletal growth and maintenance. GH- and IGF-based therapies provide a useful avenue of approach for the prevention and treatment of diseases such as osteoporosis.

| S-EPMC4808510 | biostudies-literature

Stratification of a Phelan-McDermid Syndrome Population Based on Their Response to Human Growth Hormone and Insulin-like Growth Factor.

Project description:Phelan-McDermid syndrome (PMS), caused by pathogenic variants in the SHANK3 gene or 22q13 deletions, is characterized by intellectual disability, autistic features, developmental delays, and neonatal hypotonia. Insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) have been shown to reverse neurobehavioral deficits in PMS. We assessed the metabolic profiling of 48 individuals with PMS and 50 controls and determined subpopulations by taking the top and bottom 25% of responders to hGH and IGF-1. A distinct metabolic profile for individuals with PMS showed a reduced ability to metabolize major energy sources and a higher metabolism of alternative energy sources. The analysis of the metabolic response to hGH or IGF-1 highlighted a major overlap between both high and low responders, validating the model and suggesting that the two growth factors share many target pathways. When we investigated the effect of hGH and IGF-1 on the metabolism of glucose, the correlation between the high-responder subgroups showed less similarity, whereas the low-responders were still relatively similar. Classification of individuals with PMS into subgroups based on responses to a compound can allow an investigation into pathogenic mechanisms, the identification of molecular biomarkers, an exploration of in vitro responses to candidate drugs, and eventually the selection of better candidates for clinical trials.

| S-EPMC9956088 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data