GHR
Growth hormone receptor precursor (GH receptor) (Somatotropin receptor) [Contains: Growth hormone-binding protein (GH-binding protein) (GHBP) (Serum-binding protein)]
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Growth hormone (GH) signaling plays a key role in mediating growth, development, metabolism, and lifespan regulation. However, the mechanisms of longevity regulation at the cellular and molecular level are still not well-understood. An important area in the field of GH research is in the development of advanced transgenic systems for conditional expression of GH signaling in a cell type- or tissue-specific manner. There have been many recent studies conducted to examine the effects of tissue-specific GHR disruption. This review updates our previous discussions on this topic and summarizes recent data on the newly-made tissue-specific GHR-KO mice including intestinal epithelial cells, bone, hematopoietic stem cells, cardiac myocytes, and specific brain regions. The data from these new genetically-engineered mice have a significant impact on our understanding of the local GH signaling function.
Keywords
- aging
- growth hormone
- longevity
- metabolism
- mice
We previously identified 529 proteins that had been reported by multiple different studies to change their expression level with age in human plasma. In the present study, we measured the q-value and age coefficient of these proteins in a plasma proteomic dataset derived from 4263 individuals. A bioinformatics enrichment analysis of proteins that significantly trend toward increased expression with age strongly implicated diverse inflammatory processes. A literature search revealed that at least 64 of these 529 proteins are capable of regulating life span in an animal model. Nine of these proteins (AKT2, GDF11, GDF15, GHR, NAMPT, PAPPA, PLAU, PTEN, and SHC1) significantly extend life span when manipulated in mice or fish. By performing machine-learning modeling in a plasma proteomic dataset derived from 3301 individuals, we discover an ultra-predictive aging clock comprised of 491 protein entries. The Pearson correlation for this clock was 0.98 in the learning set and 0.96 in the test set while the median absolute error was 1.84 years in the learning set and 2.44 years in the test set. Using this clock, we demonstrate that aerobic-exercised trained individuals have a younger predicted age than physically sedentary subjects. By testing clocks associated with 1565 different Reactome pathways, we also show that proteins associated with signal transduction or the immune system are especially capable of predicting human age. We additionally generate a multitude of age predictors that reflect different aspects of aging. For example, a clock comprised of proteins that regulate life span in animal models accurately predicts age.
Keywords
- age-related disease
- aging
- aging clock
- health span
- life span
- longevity
Altered adipose tissue may contribute to the longevity of Snell dwarf and growth hormone receptor (GHR) knock-out mice. We report here that white (WAT) and brown (BAT) fat have elevated UCP1 in both kinds of mice, and that adipocytes in WAT depots turn beige/brown. These imply increased thermogenesis and are expected to lead to improved glucose control. Both kinds of long-lived mice show lower levels of inflammatory M1 macrophages and higher levels of anti-inflammatory M2 macrophages in BAT and WAT, with correspondingly lower levels of TNFα, IL-6, and MCP1. Experiments with mice with tissue-specific disruption of GHR showed that these adipocyte and macrophage changes were not due to hepatic IGF1 production nor to direct GH effects on adipocytes, but instead reflect GH effects on muscle. Muscles deprived of GH signals, either globally (GKO) or in muscle only (MKO), produce higher levels of circulating irisin and its precursor FNDC5. The data thus suggest that the changes in adipose tissue differentiation and inflammatory status seen in long-lived mutant mice reflect interruption of GH-dependent irisin inhibition, with consequential effects on metabolism and thermogenesis.
Keywords
- adipose tissue
- aging
- growth hormone
- inflammation
- uncoupling protein 1 (UCP1)
We analyzed the small RNA transcriptome from 5-month-old, 24-month-old, and 36-month-old mouse liver and found 56 miRNAs that changed their expression profile with age. Among these is a cluster of 18 miRNAs that are upregulated between 50- and 1,000-fold at 24 and 36 months of age. This cluster is located in a 60-kb region of the X-chromosome that is devoid of other coding sequences and is part of a lamin-associated domain. Potential targets of the miRNAs in the cluster suggest they may regulate several pathways altered in aging, including the PI3K-Akt pathway. Total transcriptome analyses indicate that expression of several potential genes in the PI3K-Akt pathway that may be targeted by the mir-465 family (mmu-mir-465a, mmu-mir-465b, and mmu-mir-465c) is downregulated with age. Transfection of the liver cell line AML12 with mir-465 family members leads to a reduction of three of these potential targets at the mRNA level: a 40% reduction of the growth hormone receptor (GHR), and a 25% reduction in Kitl and PPP2R3C. Further investigation of the GHR 3'UTR revealed that the mir-465 family directly targets the GHR mRNA. Cells transfected with mir-465 showed a reduction of JAK2 and STAT5 phosphorylation upon growth hormone (GH) stimulation, resulting in a reduction in insulin-like growth factor 1 (IGF-1) and IGF-1-binding protein 3 expression. With age, GH signaling falls and there is a reduction in circulating IGF-1. Our data suggest that an increase in expression of the mir-465 family with age may contribute to the reduction in the GH signaling.
MeSH Terms
- Aging
- Animals
- Growth Hormone
- HEK293 Cells
- High-Throughput Nucleotide Sequencing
- Humans
- Liver
- Male
- Mice
- Mice, Inbred C57BL
- MicroRNAs
- Signal Transduction
- Up-Regulation
Keywords
- aging
- growth hormone receptor
- growth hormone signaling
- liver
- miRNAs
- mouse
To study the effect of aging and granulosa cell growth hormone receptor (GHR) expression, and the effect of growth hormone (GH) co-treatment during IVF on receptor expression. Laboratory study. University. A total of 445 follicles were collected from 62 women undergoing standard infertility treatment. Preovulatory ovarian follicle biopsies of granulosa cells and follicular fluid. Older women with a poor ovarian reserve were co-treated with GH to determine the effect of the adjuvant during IVF on the granulosal expression density of FSH receptor (FSHR), LH receptor (LHR), bone morphogenetic hormone receptor (BMPR1B), and GHR. Ovarian reserve, granulosa cell receptor density, oocyte quality, and pregnancy and live birth rates were determined. Growth hormone co-treatment increased the receptor density for granulosal FSHR, BMPR1B, LHR, and GHR compared with the non-GH-treated patients of the same age and ovarian reserve. Growth hormone co-treatment increased GHR density, which may increase GHR activity. The GH co-treatment was associated with a significant increase in pregnancy rate. Growth hormone co-treatment restored the preovulatory down-regulation of FSHR, BMPR1B, and LHR density of the largest follicles, which may improve the maturation process of luteinization in older patients with reduced ovarian reserve. The fertility of the GH-treated patients improved.
MeSH Terms
- Adult
- Bone Morphogenetic Protein Receptors, Type I
- Drug Administration Schedule
- Female
- Fertilization in Vitro
- Granulosa Cells
- Human Growth Hormone
- Humans
- Infertility, Female
- Maternal Age
- Middle Aged
- Ovarian Reserve
- Pregnancy
- Pregnancy Outcome
- Pregnancy Rate
- Receptors, FSH
- Receptors, LH
- Receptors, Somatotropin
- Young Adult
Keywords
- Aging
- fertility
- growth hormone
- pregnancy rate
- receptor density
It is well documented that inhibition of mTORC1 (defined by Raptor), a complex of mechanistic target of rapamycin (mTOR), extends life span, but less is known about the mechanisms by which mTORC2 (defined by Rictor) impacts longevity. Here, rapamycin (an inhibitor of mTOR) was used in GHR-KO (growth hormone receptor knockout) mice, which have suppressed mTORC1 and up-regulated mTORC2 signaling, to determine the effect of concurrently decreased mTORC1 and mTORC2 signaling on life span. We found that rapamycin extended life span in control normal (N) mice, whereas it had the opposite effect in GHR-KO mice. In the rapamycin-treated GHR-KO mice, mTORC2 signaling was reduced without further inhibition of mTORC1 in the liver, muscle, and s.c. fat. Glucose and lipid homeostasis were impaired, and old GHR-KO mice treated with rapamycin lost functional immune cells and had increased inflammation. In GHR-KO MEF cells, knockdown of Rictor, but not Raptor, decreased mTORC2 signaling. We conclude that drastic reduction of mTORC2 plays important roles in impaired longevity in GHR-KO mice via disruption of whole-body homeostasis.
MeSH Terms
- Animals
- Cytoplasm
- Female
- Immunosuppressive Agents
- Insulin Resistance
- Longevity
- Male
- Mechanistic Target of Rapamycin Complex 1
- Mechanistic Target of Rapamycin Complex 2
- Mice
- Mice, Inbred BALB C
- Mice, Knockout
- Receptors, Somatotropin
- Signal Transduction
- Sirolimus
Keywords
- GHR-KO
- homeostasis
- longevity
- mTORC2
- rapamycin
To elucidate whether a specific tissue is responsible for the beneficial health and longevity phenotype seen in growth hormone (GH) receptor (R) knockout (GHRKO) mice, the GHR gene was disrupted specifically in insulin sensitive tissues; namely, liver, adipose, and muscle. Furthermore, to investigate if the health- and life-span effects seen in the germline GHRKO mice were replicated when GH action was ablated after puberty; young, adult onset GHRKO mice were produced and characterized. In this review, we summarized the main findings derived from these mouse lines.
MeSH Terms
- Animals
- Insulin Resistance
- Longevity
- Mice
- Mice, Knockout
- Receptors, Somatotropin
- Signal Transduction
Keywords
- Adipose tissue
- Growth hormone receptor
- IGF-I
- Liver
- Muscle
Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion ([i]d3-GHR[/i]) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of [i]d3-GHR[/i] homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; [i]P[/i] = 0.01), 152 of the Old Order Amish (16% increase; [i]P[/i] = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; [i]P[/i] = 0.14), and 61 of the French Long-Lived Study (23.5% increase; [i]P[/i] = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; [i]P[/i] = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP [i]d3[/i]/[i]d3[/i] homozygotes were 1 inch taller than the wild-type (WT) allele carriers ([i]P[/i] = 0.05) and also showed lower serum IGF-1 levels ([i]P[/i] = 0.003). Multivariate regression analysis indicated that the presence of [i]d3[/i]/[i]d3[/i] genotype adds approximately 10 years to life span. The LGP d3/[i]d3-GHR[/i] transformed lymphocytes exhibited superior growth and extracellular signal-regulated kinase activation, to GH treatment relative to WT GHR lymphocytes ([i]P[/i] < 0.01), indicating a GH dose response. The [i]d3-GHR[/i] variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity.
MeSH Terms
- Body Height
- Exons
- Female
- Genetic Association Studies
- Human Growth Hormone
- Humans
- Insulin-Like Growth Factor I
- Kaplan-Meier Estimate
- Longevity
- Male
- Phenotype
- Polymorphism, Genetic
- Quantitative Trait, Heritable
- Receptors, Somatotropin
- Sequence Deletion
Keywords
- Centenarians
- IGF-I
- d3-GHR
- growth hormone receptor
- longevity
- positive pleiotropy
There is increasing evidence that growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling (collectively referred to as somatotropic signaling) during development has a profound influence on aging and longevity. Moreover, the absence of GH action was shown to modify responses of adult mice to calorie restriction (CR) and other antiaging interventions. It was therefore of interest to determine whether GH resistance in GH receptor knockout (GHR-KO) mice would modify the effects of mild pre-weaning CR imposed by increasing the number of pups in a litter (the so-called litter crowding). In addition to the expected impact on body weight, litter crowding affected glucose homeostasis, hepatic expression of IGF-1 and genes related to lipid metabolism, and expression of inflammatory markers in white adipose tissue, with some of these effects persisting until the age of 2 years. Litter crowding failed to further extend the remarkable longevity of GHR-KO mice and, instead, reduced late life survival of GHR-KO females, an effect opposite to the changes detected in normal animals. We conclude that the absence of GH actions alters the responses to pre-weaning CR and prevents this intervention from extending longevity.
MeSH Terms
- Adipose Tissue, White
- Aging
- Animals
- Body Size
- Caloric Restriction
- Food
- Growth Hormone
- Homeostasis
- Insulin-Like Growth Factor Binding Protein 1
- Intracellular Signaling Peptides and Proteins
- Lipid Metabolism
- Longevity
- Mice
- Mice, Knockout
Keywords
- Aging
- GHR-KO
- Growth hormone
- Litter crowding
Growth hormone receptor deficiency (GHRD) results in short stature, enhanced insulin sensitivity, and low circulating levels of insulin and insulin-like growth factor 1 (IGF-1). Previous studies in mice and humans suggested that GHRD has protective effects against age-related diseases, including cancer and diabetes. Whereas GHRD mice show improved age-dependent cognitive performance, the effect of GHRD on human cognition remains unknown. Using MRI, we compared brain structure, function, and connectivity between 13 people with GHRD and 12 unaffected relatives. We assessed differences in white matter microstructural integrity, hippocampal volume, subregional volumes, and cortical thickness and surface area of selected regions. We also evaluated brain activity at rest and during a hippocampal-dependent pattern separation task. The GHRD group had larger surface areas in several frontal and cingulate regions and showed trends toward larger dentate gyrus and CA1 regions of the hippocampus. They had lower mean diffusivity in the genu of the corpus callosum and the anterior thalamic tracts. The GHRD group showed enhanced cognitive performance and greater task-related activation in frontal, parietal, and hippocampal regions compared with controls. Furthermore, they had greater functional synchronicity of activity between the precuneus and the rest of the default mode network at rest. The results suggest that, compared with controls, GHRD subjects have brain structure and function that are more consistent with those observed in younger adults reported in previous studies. Further investigation may lead to improved understanding of underlying mechanisms and could contribute to the identification of treatments for age-related cognitive deficits. People and mice with growth hormone receptor deficiency (GHRD or Laron syndrome) are protected against age-related diseases including cancer and diabetes. However, in humans, it is unknown whether cognitive function and brain structure are affected by GHRD. Using MRI, we examined cognition in an Ecuadorian population with GHRD and their unaffected relatives. The GHRD group showed better memory performance than their relatives. The differences in brain structure and function that we saw between the two groups were not consistent with variations typically associated with brain deficits. This study contributes to our understanding of the connection between growth genes and brain aging in humans and provides data indicating that GHR inhibition has the potential to protect against age-dependent cognitive decline.
MeSH Terms
- Adult
- Anisotropy
- Brain
- Female
- Genotype
- Humans
- Image Processing, Computer-Assisted
- Insulin
- Insulin-Like Growth Factor Binding Protein 1
- Insulin-Like Growth Factor I
- Laron Syndrome
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Mutation
- Neuropsychological Tests
- Oxygen
- Photic Stimulation
- Receptors, Somatotropin
- Saliva
- Young Adult
Keywords
- IGF-1
- MRI
- aging
- cognition
- growth hormone receptor deficiency
- insulin
Growth hormone receptor knockout (GHR-KO) mice are long lived with improved health span, making this an excellent model system for understanding biochemical mechanisms important to cognitive reserve. The purpose of the present study was to elucidate differences in cognition and glutamatergic dynamics between aged (20- to 24-month-old) GHR-KO and littermate controls. Glutamate plays a critical role in hippocampal learning and memory and is implicated in several neurodegenerative disorders, including Alzheimer's disease. Spatial learning and memory were assessed using the Morris water maze (MWM), whereas independent dentate gyrus (DG), CA3, and CA1 basal glutamate, release, and uptake measurements were conducted in isoflurane anesthetized mice utilizing an enzyme-based microelectrode array (MEA) coupled with constant potential amperometry. These MEAs have high temporal and low spatial resolution while causing minimal damage to the surrounding parenchyma. Littermate controls performed worse on the memory portion of the MWM behavioral task and had elevated DG, CA3, and CA1 basal glutamate and stimulus-evoked release compared with age-matched GHR-KO mice. CA3 basal glutamate negatively correlated with MWM performance. These results support glutamatergic regulation in learning and memory and may have implications for therapeutic targets to delay the onset of, or reduce cognitive decline, in Alzheimer's disease.
MeSH Terms
- Aging
- Animals
- Cognition
- Female
- Glutamic Acid
- Memory
- Mice
- Mice, Knockout
- Models, Animal
- Receptors, Somatotropin
- Signal Transduction
- Spatial Learning
Keywords
- Alzheimer’s disease
- Biosensor
- Electrode
- Health span
- Longevity
Growth hormone (GH) administration reduces abdominal, but not lower body, fat mass. To gain insight into the underlying mechanisms, this study examined the expression of the GH receptor (GHR) and some of its targets in abdominal and gluteal adipose tissue. GHR and GH targets in the lipolytic pathway were assessed (quantitative PCR/Western blotting) in adipose aspirates from premenopausal women [n = 15, age 26.9 ± 6.1 years, body mass index (BMI) 28.0 ± 6.8 kg/m(2) ] and men (n = 28, age 29.2 ± 7.0 years, BMI 26.9 ± 3.7 kg/m(2) ). GHR mRNA expression was lower in the gluteal depot when compared with the abdominal depot (P = 0.01). Abdominal GHR correlated negatively with age and BMI, whereas gluteal GHR was associated with lower waist-to-hip ratio (WHR), that is, pear shape. In both sites, GHR mRNA correlated strongly with genes important for the regulation of lipolysis: adipose tissue triglyceride lipase (ATGL), hormone-sensitive lipase, perilipin, and CIDEA (all P < 0.001), independently of BMI, WHR, age, and sex. GHR protein was lower in the gluteal fat when compared with the abdominal fat (P = 0.03) and correlated with ATGL protein in the gluteal depot (P < 0.001). GHR levels correlate with levels of lipases and lipid droplet-associated proteins crucial for lipolysis. Thus, higher GHR expression in the abdominal depot when compared with the gluteal depot may underlie the in vivo effect of GH to specifically reduce abdominal adipose tissue mass.
MeSH Terms
- Adipose Tissue
- Adiposity
- Adult
- Aging
- Body Mass Index
- Buttocks
- Carrier Proteins
- Female
- Gene Expression
- Human Growth Hormone
- Humans
- Lipase
- Lipolysis
- Male
- Obesity
- Premenopause
- RNA, Messenger
- Receptors, Somatotropin
- Subcutaneous Fat, Abdominal
- Waist-Hip Ratio
Reduced somatotropic [growth hormone (GH) and insulin-like growth factor-1 (IGF-1)] action has been associated with delayed and slower aging, reduced risk of frailty, reduced age-related disease and functional decline, and with remarkably extended longevity. Recent studies have added to the evidence that these relationships discovered in laboratory populations of mice apply to other mammalian species. However, the relationship of the somatotropic signaling to human aging is less striking, complex and controversial. In mice, targeted deletion of GH receptors (GHR) in the liver, muscle or adipose tissue affected multiple metabolic parameters but failed to reproduce the effects of global GHR deletion on longevity. Continued search for mechanisms of extended longevity in animals with GH deficiency or resistance focused attention on different pathways of mechanistic target of rapamycin (mTOR), energy metabolism, regulation of local IGF-1 levels and resistance to high-fat diet (HFD).
MeSH Terms
- Aging
- Animals
- Endocrine System
- Energy Metabolism
- Growth Hormone
- Humans
- Insulin-Like Growth Factor I
- Longevity
- Mice
- Receptors, Somatotropin
Keywords
- Adipose tissue
- Growth hormone
- Growth hormone receptors
- IGF-1
- Liver
- Longevity
- Muscle
Simple organisms including yeast and flies with mutations in the IGF-1 and Tor-S6K pathways are dwarfs, are highly protected from toxins, and survive up to 3 times longer. Similarly, dwarf mice with deficiencies in the growth hormone-IGF-I axis are also long lived and protected from diseases. We recently reported that humans with Growth Hormone Receptor Deficiency (GHRD) rarely develop cancer or diabetes. These findings are in agreement with the effect of defects in the Tor-S6K pathways in causing dwarfism and protection of DNA. Because protein restriction reduces both GHR-IGF-1 axis and Tor-S6K activity, we examined links between protein intake, disease, and mortality in over 6000 US subjects in the NHANES CDC database. Respondents aged 50-65 reporting a high protein intake displayed an increase in IGF-I levels, a 75% increased risk of overall mortality and a 3-4 fold increased risk of cancer mortality in agreement with findings in mouse experiments. These studies point to a conserved link between proteins and amino acids, GHR-IGF-1/insulin, Tor-S6k signaling, aging, and diseases.
MeSH Terms
- Aging
- Animals
- Caloric Restriction
- Diabetes Mellitus
- Diet, Protein-Restricted
- Growth Hormone
- Humans
- Insulin-Like Growth Factor I
- Longevity
- Neoplasms
- Receptors, Somatotropin
- Ribosomal Protein S6 Kinases
- Signal Transduction
- TOR Serine-Threonine Kinases
Keywords
- Amino acids
- Calorie restriction
- Growth
- Growth hormone
- Growth hormone receptor deficiency
- IGF-1
- Proteins
- Ras
- TOR
Animal growth and development are complex and sophisticated biological metabolic processes, in which genes plays an important role. In this paper, we employed real-time quantitative PCR (RT-qPCR) to analyze the expression levels of hepatic GHR, JAK2 and IGF-I genes in 1, 30, 180 day of Bama minipig and Landrace with attempt to verify the correlation between the expression of these growth-associated genes and the dwarfism phenotype of Bama minipig. The results showed that the expression levels of these 3 genes in Bama minipigs were down-regulated expressed from 1 day to 30 day, and which was up-regulated expressed in Landrace. The expression levels of the 3 genes on 1, 30, 180 day were prominently higher in Landrace than in Bama minipigs. The significant differences of the 3 genes expression levels on 1 day between this two breeds indicate that different expressions of these genes might occur before birth. It is speculated that the down-regulated expression of the 3 genes may have a close correlation with the dwarfism phenotype of Bama minipig. More investigations in depth of this study is under progress with the help of biochip nanotechnology.
MeSH Terms
- Aging
- Animals
- Dwarfism
- Gene Expression Regulation, Developmental
- Insulin-Like Growth Factor I
- Janus Kinase 2
- Liver
- Phenotype
- Receptors, Somatotropin
- Species Specificity
- Swine
- Swine, Miniature
Mice in which the genes for growth hormone (GH) or GH receptor (GHR(-/-) ) are disrupted from conception are dwarfs, possess low levels of IGF-1 and insulin, have low rates of cancer and diabetes, and are extremely long-lived. Median longevity is also increased in mice with deletion of hypothalamic GH-releasing hormone (GHRH), which leads to isolated GH deficiency. The remarkable extension of longevity in hypopituitary Ames dwarf mice can be reversed by a 6-week course of GH injections started at the age of 2 weeks. Here, we demonstrate that mutations that interfere with GH production or response, in the Snell dwarf, Ames dwarf, or GHR(-/-) mice lead to reduced formation of both orexigenic agouti-related peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) projections to the main hypothalamic projection areas: the arcuate nucleus (ARH), paraventricular nucleus (PVH), and dorsomedial nucleus (DMH). These mutations also reduce hypothalamic inflammation in 18-month-old mice. GH injections, between 2 and 8 weeks of age, reversed both effects in Ames dwarf mice. Disruption of GHR specifically in liver (LiGHRKO), a mutation that reduces circulating IGF-1 but does not lead to lifespan extension, had no effect on hypothalamic projections or inflammation, suggesting an effect of GH, rather than peripheral IGF-1, on hypothalamic development. Hypothalamic leptin signaling, as monitored by induction of pStat3, is not impaired by GHR deficiency. Together, these results suggest that early-life disruption of GH signaling produces long-term hypothalamic changes that may contribute to the longevity of GH-deficient and GH-resistant mice.
MeSH Terms
- Agouti-Related Protein
- Animals
- Arcuate Nucleus of Hypothalamus
- Carrier Proteins
- Dwarfism, Pituitary
- Growth Hormone
- Inflammation
- Insulin
- Insulin-Like Growth Factor I
- Leptin
- Liver
- Longevity
- Male
- Mediodorsal Thalamic Nucleus
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Paraventricular Hypothalamic Nucleus
- Pro-Opiomelanocortin
- STAT3 Transcription Factor
Keywords
- aging
- dwarf mice
- growth hormone
- hypothalamus
- inflammation
- longevity
Global disruption of the GH receptor in mice (GHR-/-) produces a large and reproducible extension in lifespan. Since lack of GH action in muscle resulting in improved glucose homeostasis is potentially a mechanism by which GHR-/- mice are long-lived, and since no information on muscle-specific GHR disruption in females is available, we generated and characterized a line of muscle-specific GHR disrupted (MuGHRKO) mice. As expected, male MuGHRKO mice had improved fasting blood glucose, insulin, c-peptide, and glucose tolerance. In contrast, female MuGHRKO mice exhibited normal glucose, insulin, and glucose tolerance. Body weight was mildly but significantly altered in opposite directions in males (decreased) and females (increased) compared to controls. Grip strength and treadmill endurance were unchanged with advanced age in both sexes, suggesting that the direct action of GH on muscle has minimal effect on age-related musculoskeletal frailty. Longevity was unchanged in both sexes at Ohio University and significantly increased for males at University of Michigan. These data suggest that removal of GHR in muscle of male MuGHRKO mice replicates some of the health benefits seen in global GHR-/- mice including improvements to glucose homeostasis and smaller body weight in males, which may explain the trends observed in lifespan.
MeSH Terms
- Animals
- Blood Glucose
- Body Composition
- Body Weight
- C-Peptide
- Carrier Proteins
- Energy Metabolism
- Female
- Glucose Intolerance
- Health Status
- Insulin
- Longevity
- Male
- Mice
- Mice, Knockout
- Muscle Strength
- Muscle, Skeletal
- Physical Endurance
- Sex Characteristics
Mitochondrial biogenesis is an essential process for cell viability. Mice with disruption of the growth hormone receptor (GHR) gene (Ghr gene) in the liver (LiGHRKO), in contrast to long-lived mice with global deletion of the Ghr gene (GHRKO), are characterized by lack of improved insulin sensitivity and severe hepatic steatosis. Tissue-specific disruption of the GHR in liver results in a mouse model with dramatically altered GH/IGF1 axis. We have previously shown increased levels of key regulators of mitochondrial biogenesis in insulin-sensitive GHRKO mice. The aim of the present study is to assess, using real-time PCR, the gene expression of key regulators of mitochondrial biogenesis (Pgc1α, Ampk, Sirt1, Nrf2 and Mfn2) and a marker of mitochondrial activity (CoxIV) in brains, kidneys and livers of male and female LiGHRKO and wild-type (WT) mice. There were significant differences between males and females. In the brain, expression of Pgc1α, Ampk, Sirt1, Nrf2 and Mfn2 was lower in pooled females compared to pooled males. In the kidneys, expression of Ampk and Sirt1 was also lower in female mice. In the liver, no differences between males and females were observed. Sexual dimorphism may play an important role in regulating the biogenesis of mitochondria.
MeSH Terms
- AMP-Activated Protein Kinases
- Aging
- Animals
- Brain
- Electron Transport Complex IV
- Female
- GA-Binding Protein Transcription Factor
- GTP Phosphohydrolases
- Gene Expression
- Kidney
- Liver
- Male
- Mice, Knockout
- Mitochondrial Turnover
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Receptors, Somatotropin
- Sex Characteristics
- Sirtuin 1
- Transcription Factors
Keywords
- gene disruption
- growth hormone receptor
- knockout mice
- mitochondrial biogenesis
- sexual dimorphism
- tissue-specific gene disruption
{{medline-entry |title=Interaction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25789159 |abstract=The correlation of physiological sensitivity to insulin ( vis-à-vis glycemic regulation) and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity). The growth hormone receptor/ binding protein gene-disrupted (GHR-KO) mouse is the most extensively investigated insulin-sensitive, attenuated aging model. It was reported that, in a manner divergent from similar mutants, GHR-KO mice fail to respond to caloric restriction (CR) by altering their insulin sensitivity. We hypothesized that maximized insulin responsiveness is what causes GHR-KO mice to exhibit a suppressed survivorship response to dietary (including caloric) restriction; and attempted to refute this hypothesis by assessing the effects of CR on GHR-KO mice for varied slow-aging-associated phenotypes. In contrast to previous reports, we found GHR-KO mice on CR to be less responsive than their ad libitum (A.L.) counterparts to the hypoglycemia-inducing effects of insulin. Further, CR had negligible effects on the metabolism or cognition of GHR-KO mice. Therefore, our data suggest that the effects of CR on the insulin sensitivity of GHR-KO mice do not concur with the effects of CR on the aging of GHR-KO mice.
|keywords=Longevity regulation; endocrinology