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1.  Expression levels of insulin-like growth factor 1 and 2 in head and neck squamous cell carcinoma 
Insulin-like growth factors (IGF) 1 and 2 are known as potential mitogens for normal and neoplastic cells. IGF2 is a main fetal growth factor while IGF1 is activated through growth hormone action during postnatal growth and development. However, there is strong evidence that activation of IGF2 by its E2F transcription factor 3 (E2F3) is present in different types of cancer. Also high levels of IGF1 strongly correlate with cancer development due to anti-apoptotic properties and enhancement of cancer cell differentiation, which can be attenuated by IGFBP3. Head and neck cancer is known as one of the six most common human cancers. The main risk factor for head and neck cancer is consumption of tobacco and alcohol as well as viral and bacterial infection by stimulation of chronic local inflammation. There is also a genetic basis for this form of cancer; however, the genetic markers are not yet established. In this study we investigated the levels of the expression of IGF2, IGF1, E2F3 and IGFBP3 in human cancers and healthy tissues surrounding the tumor obtained from each of 41 patients. Our study indicated that there is no alteration of the level of expression of IGF2, E2F3 and IGF1 in Head and neck squamous cell carcinoma (HNSCC) cases studied in selected experimental population, but there was evidence for upregulation of pro-apoptotic IGFBP3 in cancer when comparing to healthy tissue. These important findings indicate that insulin-growth factors are not directly associated with HNSCC showing some variability between patients and location of tumor. However, elevated level of IGFBP3 suggests possible regulatory role of IGF signal by its binding protein in this type of tumors.
doi:10.1016/j.ghir.2014.04.003
PMCID: PMC4083007  PMID: 24802266
oral cancer; IGF1; IGF2; survival
2.  Growth hormone, inflammation and aging 
Pathobiology of Aging & Age Related Diseases  2012;2:10.3402/pba.v2i0.17293.
Mutant animals characterized by extended longevity provide valuable tools to study the mechanisms of aging. Growth hormone and insulin-like growth factor-1 (IGF-1) constitute one of the well-established pathways involved in the regulation of aging and lifespan. Ames and Snell dwarf mice characterized by GH deficiency as well as growth hormone receptor/growth hormone binding protein knockout (GHRKO) mice characterized by GH resistance live significantly longer than genetically normal animals. During normal aging of rodents and humans there is increased insulin resistance, disruption of metabolic activities and decline of the function of the immune system. All of these age related processes promote inflammatory activity, causing long term tissue damage and systemic chronic inflammation. However, studies of long living mutants and calorie restricted animals show decreased pro-inflammatory activity with increased levels of anti-inflammatory adipokines such as adiponectin. At the same time, these animals have improved insulin signaling and carbohydrate homeostasis that relate to alterations in the secretory profile of adipose tissue including increased production and release of anti-inflammatory adipokines. This suggests that reduced inflammation promoting healthy metabolism may represent one of the major mechanisms of extended longevity in long-lived mutant mice and likely also in the human.
doi:10.3402/pba.v2i0.17293
PMCID: PMC3417471  PMID: 22953033
Ghowth hormone; obesity; inflammation; calorie restriction; aging
3.  The contribution of visceral fat to improved insulin signaling in Ames dwarf mice 
Aging cell  2014;13(3):497-506.
SUMMARY
Ames dwarf (Prop1df, df/df) mice are characterized by growth hormone (GH), prolactin and thyrotropin deficiency, remarkable extension of longevity and increased insulin sensitivity with low levels of fasting insulin and glucose. Plasma levels of anti-inflammatory adiponectin are increased in df/df mice while pro-inflammatory IL-6 was decreased in plasma and epididymal fat. This represents an important shift in the balance between pro- and anti-inflammatory adipokines in adipose tissue, which was not exposed to GH signals during development or adult life. To determine the role of adipose tissue in the control of insulin signaling in these long living mutants, we examined the effects of surgical removal of visceral (epididymal and perinephric) adipose tissue. Comparison of the results obtained in df/df mice and their normal (N) siblings indicated different effects of visceral fat removal (VFR) on insulin sensitivity and glucose tolerance. The analysis of the expression of genes related to insulin signaling indicated that VFR improved insulin action in skeletal muscle in N mice. Interestingly, this surgical intervention did not improve insulin signaling in df/df mice skeletal muscle but caused suppression of the signal in subcutaneous fat. We conclude that altered profile of adipokines secreted by visceral fat of Ames dwarf mice may act as a key contributor to increased insulin sensitivity and extended longevity of these animals.
doi:10.1111/acel.12201
PMCID: PMC4032618  PMID: 24690289
Ames dwarf; insulin; adipose tissue; adiponectin; obesity
4.  Thyroxine modifies the effects of growth hormone in Ames dwarf mice 
Aging (Albany NY)  2015;7(4):241-255.
Ames dwarf (df/df) mice lack growth hormone (GH), thyroid stimulating hormone and prolactin. Treatment of juvenile df/df mice with GH alone stimulates somatic growth, reduces insulin sensitivity and shortens lifespan. Early‐life treatment with thyroxine (T4) alone produces modest growth stimulation but does not affect longevity. In this study, we examined the effects of treatment of juvenile Ames dwarf mice with a combination of GH + T4 and compared them to the effects of GH alone. Treatment of female and male dwarfs with GH + T4 between the ages of 2 and 8 weeks rescued somatic growth yet did not reduce lifespan to match normal controls, thus contrasting with the previously reported effects of GH alone. While the male dwarf GH + T4 treatment group had no significant effect on lifespan, the female dwarfs undergoing treatment showed a decrease in maximal longevity. Expression of genes related to GH and insulin signaling in the skeletal muscle and white adipose tissue (WAT) of female dwarfs was differentially affected by treatment with GH + T4 vs. GH alone. Differences in the effects of GH + T4 vs. GH alone on insulin target tissues may contribute to the differential effects of these treatments on longevity.
PMCID: PMC4429089  PMID: 25935838
5.  Gene expression analysis of head and neck squamous cell carcinoma survival and recurrence 
Oncotarget  2014;6(1):547-555.
The squamous cell carcinomas represent about 90 % of all head and neck cancers, ranking the sixth most common human cancer. Approximately 450,000 of new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed every year. Unfortunately, because of diagnosis at the advanced stages and early metastasis to the lymph nodes, the HNSCC is associated with very high death rate. Identification of signature biomarkers and molecularly targeted therapies could provide more effective and specific cancer treatment, prevent recurrence, and increase survival rate. We used paired tumor and adjacent normal tissue samples to screen with RT² Profiler™ PCR Array Human Cancer PathwayFinderTM. Total of 20 up-regulated genes and two down-regulated genes were screened out. Out of 22 genes, 12 genes were subsequently validated to be significantly altered in the HNSCC; the samples were from all 41 patients. Five year survival and recurrence selected genes that could represent the biomarkers of survival and recurrence of the disease. We believe that comprehensive understanding of the unique genetic characteristics of HNSCC could provide novel diagnostic biomarkers and meet the requirement for molecular-targeted therapy for the HNSCC.
PMCID: PMC4381614  PMID: 25575813
PCR array; cancer pathway; gene expression; oral cancer
6.  The effect of calorie restriction on insulin signaling in skeletal muscle and adipose tissue of Ames dwarf mice 
Aging (Albany NY)  2014;6(10):900-912.
Long-living Ames dwarf (df/df) mice are homozygous for a mutation of the Prop1df gene. As a result, mice are deficient in growth hormone (GH), prolactin (PRL) and thyrotropin (TSH). In spite of the hormonal deficiencies, df/df mice live significantly longer and healthier lives compared to their wild type siblings. We studied the effects of calorie restriction (CR) on the expression of insulin signaling genes in skeletal muscle and adipose tissue of normal and df/df mice. The analysis of genes expression showed that CR differentially affects the insulin signaling pathway in these insulin target organs. Moreover, results obtained in both normal and Ames dwarf mice indicate more direct effects of CR on insulin signaling genes in adipose tissue than in skeletal muscle. Interestingly, CR reduced the protein levels of adiponectin in the epididymal adipose tissue of normal and Ames dwarf mice, while elevating adiponectin levels in skeletal muscle and plasma of normal mice only.
In conclusion, our findings suggest that both skeletal muscle and adipose tissue are important mediators of insulin effects on longevity. Additionally, the results revealed divergent effects of CR on expression of genes in the insulin signaling pathway of normal and Ames dwarf mice.
PMCID: PMC4247389  PMID: 25411241
Ames dwarf; insulin; adipose tissue; skeletal muscle; adiponectin; obesity
7.  The contribution of visceral fat to improved insulin signaling in Ames dwarf mice 
Aging Cell  2014;13(3):497-506.
Ames dwarf (Prop1df, df/df) mice are characterized by growth hormone (GH), prolactin, and thyrotropin deficiency, remarkable extension of longevity and increased insulin sensitivity with low levels of fasting insulin and glucose. Plasma levels of anti-inflammatory adiponectin are increased in df/df mice, while pro-inflammatory IL-6 is decreased in plasma and epididymal fat. This represents an important shift in the balance between pro- and anti-inflammatory adipokines in adipose tissue, which was not exposed to GH signals during development or adult life. To determine the role of adipose tissue in the control of insulin signaling in these long-living mutants, we examined the effects of surgical removal of visceral (epididymal and perinephric) adipose tissue. Comparison of the results obtained in df/df mice and their normal (N) siblings indicated different effects of visceral fat removal (VFR) on insulin sensitivity and glucose tolerance. The analysis of the expression of genes related to insulin signaling indicated that VFR improved insulin action in skeletal muscle in N mice. Interestingly, this surgical intervention did not improve insulin signaling in df/df mice skeletal muscle but caused suppression of the signal in subcutaneous fat. We conclude that altered profile of adipokines secreted by visceral fat of Ames dwarf mice may act as a key contributor to increased insulin sensitivity and extended longevity of these animals.
doi:10.1111/acel.12201
PMCID: PMC4032618  PMID: 24690289
adiponectin; adipose tissue; Ames dwarf; insulin; obesity
8.  Metabolic effects of intra-abdominal fat in GHRKO mice 
Aging Cell  2011;11(1):73-81.
SUMMARY
Mice with targeted deletion of the growth hormone receptor (GHRKO mice) are GH resistant, small, obese, hypoinsulinemic, highly insulin sensitive and remarkably long-lived. To elucidate the unexpected coexistence of adiposity with improved insulin sensitivity and extended longevity, we examined effects of surgical removal of visceral (epididymal and perinephric) fat on metabolic traits related to insulin signaling and longevity. Comparison of results obtained in GHRKO mice and in normal animals from the same strain revealed disparate effects of visceral fat removal (VFR) on insulin and glucose tolerance, adiponectin levels, accumulation of ectopic fat, phosphorylation of insulin signaling intermediates, body temperature and respiratory quotient (RQ). Overall, VFR produced the expected improvements in insulin sensitivity and reduced body temperature and RQ in normal mice and had opposite effects in GHRKO mice. Some of the examined parameters were altered by VFR in opposite directions in GHRKO and normal mice, others were affected in only one genotype or exhibited significant genotype × treatment interactions. Functional differences between visceral fat of GHRKO and normal mice were confirmed by measurements of adipokine secretion, lipolysis and expression of genes related to fat metabolism. We conclude that in the absence of GH signaling the secretory activity of visceral fat is profoundly altered and unexpectedly promotes enhanced insulin sensitivity. The apparent beneficial effects of visceral fat in GHRKO mice may also explain why reducing adiposity by calorie restriction fails to improve insulin signaling or further extend longevity in these animals.
doi:10.1111/j.1474-9726.2011.00763.x
PMCID: PMC3257405  PMID: 22040032
GHRKO; insulin; adipose tissue
9.  Caloric Restriction and Growth Hormone Receptor Knockout: Effects on Expression of Genes Involved in Insulin Action in the Heart 
Experimental gerontology  2006;41(4):417-429.
Blockade of growth hormone (GH), decreased insulin-like growth factor-1 (IGF1) action and increased insulin sensitivity are associated with life extension and an apparent slowing of the aging process. We examined expression of genes involved in insulin action, IR, IRS1, IRS2, IGF1, IGF1R, GLUT4, PPARs and RXRs in the hearts of normal and GHR−/− (KO) mice fed ad libitum or subjected to 30% caloric restriction (CR). CR increased the cardiac expression of IR, IRS1, IGF1, IGF1R and GLUT4 in normal mice and IRS1, GLUT4, PPARα and PPARβ/δ in GHR-KO animals. Expression of IR, IRS1, IRS2, IGF1, GLUT4, PPARγ and PPARα did not differ between GHR-KO and normal mice. These unexpected results suggest that CR may lead to major modifications of insulin action in the heart, but high insulin sensitivity of GHR-KO mice is not associated with alterations in the levels of most of the examined molecules related to intracellular insulin signaling.
doi:10.1016/j.exger.2006.01.009
PMCID: PMC3082456  PMID: 16524678
Caloric restriction; aging; GHR-KO; insulin; fatty acid
10.  Effects of Growth Hormone and Thyroxine Replacement Therapy on Insulin Signaling in Ames Dwarf Mice 
Ames dwarf (Prop1df, df/df) mice lack growth hormone (GH), prolactin, and thyrotropin and live remarkably longer than their normal siblings. Significance of reduced activity of the somatotropic and thyroid axes during development and adulthood on longevity are unknown. Because enhanced insulin sensitivity and reduced insulin levels are among likely mechanisms responsible for increased longevity in these mutants, we compared the effects of GH and thyroxine (T4) replacement on various parameters related to insulin signaling in young and old male df/df mice. The results suggest that altered plasma adiponectin and insulin-like growth factor-1 (IGF-1) and hepatic IGF-1, insulin receptor (IR), IR substrate-1, peroxisome proliferator–activated receptor (PPAR) γ, and PPARγ coactivator-1 α may contribute to increased insulin sensitivity in Ames dwarfs. The stimulatory effect of GH and T4 treatment on plasma insulin and inhibitory effect on expression of hepatic glucose transporter-2 were greater in old than in young dwarfs. These results indicate that GH and T4 treatment has differential impact on insulin signaling during development and adulthood.
doi:10.1093/gerona/glq018
PMCID: PMC2844062  PMID: 20200088
Ames dwarf; Aging; Insulin; Growth hormone
11.  The Effects of Growth Hormone (GH) Treatment on GH and Insulin/IGF-1 Signaling in Long-Lived Ames Dwarf Mice 
The disruption of the growth hormone (GH) axis in mice promotes insulin sensitivity and is strongly correlated with extended longevity. Ames dwarf (Prop1df, df/df) mice are GH, prolactin (PRL), and thyrotropin (TSH) deficient and live approximately 50% longer than their normal siblings. To investigate the effects of GH on insulin and GH signaling pathways, we subjected these dwarf mice to twice-daily GH injections (6 μg/g/d) starting at the age of 2 weeks and continuing for 6 weeks. This produced the expected activation of the GH signaling pathway and stimulated somatic growth of the Ames dwarf mice. However, concomitantly with increased growth and increased production of insulinlike growth factor-1, the GH treatment strongly inhibited the insulin signaling pathway by decreasing insulin sensitivity of the dwarf mice. This suggests that improving growth of these animals may negatively affect both their healthspan and longevity by causing insulin resistance.
doi:10.1093/gerona/glp172
PMCID: PMC2796883  PMID: 19906822
Ames dwarf; Aging; Insulin; Growth hormone
12.  Is Altered Expression of Hepatic Insulin-Related Genes in Growth Hormone Receptor Knockout Mice Due to GH Resistance or a Difference in Biological Life Spans? 
Growth hormone receptor knockout (GHRKO) mice live about 40%–55% longer than their normal (N) littermates. Previous studies of 21-month-old GHRKO and N mice showed major alterations of the hepatic expression of genes involved in insulin signaling. Differences detected at this age may have been caused by the knockout of the growth hormone receptor (GHR) or by differences in biological age between GHRKO and N mice. To address this question, we compared GHRKO and N mice at ages corresponding to the same percentage of median life span to see if the differences of gene expression persisted. Comparison of GHRKO and N mice at ∼50% of biological life span showed significant differences in hepatic expression of all 14 analyzed genes. We conclude that these changes are due to disruption of GHR gene and the consequent suppression of growth hormone signaling rather than to differences in “biological age” between mutant and normal animals sampled at the same chronological age.
doi:10.1093/gerona/glp111
PMCID: PMC2759569  PMID: 19706698
Aging; GHRKO; Insulin
13.  Insulin Sensitivity as a Key Mediator of Growth Hormone Actions on Longevity 
Reduced insulin sensitivity and glucose intolerance have been long suspected of having important involvement in aging. Here we report that in studies of calorie restriction (CR) effects in mutant (Prop1df and growth hormone receptor knockout [GHRKO]) and normal mice, insulin sensitivity was strongly associated with longevity. Of particular interest was enhancement of the already increased insulin sensitivity in CR df/df mice in which longevity was also further extended and the lack of changes in insulin sensitivity in calorically restricted GHRKO mice in which there was no further increase in average life span. We suggest that enhanced insulin sensitivity, in conjunction with reduced insulin levels, may represent an important (although almost certainly not exclusive) mechanism of increased longevity in hypopituitary, growth hormone (GH)-resistant, and calorie-restricted animals. We also report that the effects of GH treatment on insulin sensitivity may be limited to the period of GH administration.
doi:10.1093/gerona/glp024
PMCID: PMC2667133  PMID: 19304940
Insulin; Longevity; GHRKO; Ames dwarf
14.  Circulating blood leukocyte gene expression profiles: Effects of the Ames dwarf mutation on pathways related to immunity and inflammation 
Experimental gerontology  2007;42(8):772-788.
Aging is associated with a decline of immune competence and an increase in markers of inflammation. There is considerable evidence that inflammatory processes play a role in aging and the determination of lifespan. Hypopituitary Ames dwarf mice have extended longevity and exhibit many symptoms of delayed aging, although various aspects of immune function are suppressed in the mutants. In the present study, the expression of genes related to immunity and inflammation was compared in peripheral blood leukocytes (PBL) from Ames dwarf and normal mice using Affymetrix Gene Chip arrays. Among the more than 3000 probe sets that were differentially expressed, 273 were identified as being associated with immunity and/or inflammation. Pathway analysis revealed interactions among 91 of these probe sets, centered on casp3, bcl2, il4, prkca, mapk14, and TGFβ1. Ames dwarf mice had reduced leukocyte expression of casp3 and TGFβ and increased expression of Bcl2. Alterations in the expression of these genes suggest likely functional changes in apoptosis, B and T cell homeostasis, prostaglandin synthesis, humoral immunity, chemokine activity, complement activation, hemostasis and wound healing pathways. Collectively, these results suggest that activation of both anti-inflammatory pathways and an anti-clotting mechanism combined with reduced turnover of leukocytes may contribute to delayed aging and extended longevity of Ames dwarf mice. We are also aware that alterations in gene expression in PBLs can be due to different composition of PBL populations when comparing Ames dwarf to WT animals, and it will be interesting to investigate these genes in particular PBL populations in the future. However, whole leucocytes population represents the function of immune system in these organisms.
doi:10.1016/j.exger.2007.04.004
PMCID: PMC2045642  PMID: 17611063
Ames dwarf; aging; PBL; inflammation
15.  Effect of growth hormone receptor gene disruption and PMA treatment on the expression of genes involved in primordial follicle activation in mice ovaries 
Age  2014;36(4):9701.
The activation of the Pi3k-Akt1-FOXO pathway seems to be involved in the extended longevity observed in growth hormone receptor/growth hormone binding protein knockout (GHRKO) mice and is related to the growth of primordial ovarian follicles. The aim of this work was to measure the expression of genes in the ovaries of GHRKO and normal (N) mice treated with phorbol 12-myristate 13-acetate (PMA), an inhibitor of GH and IRS1 signaling. For this study, a group of N (n = 10) and GHRKO (n = 10) mice, N mice treated (n = 10) or not (n = 10) with PMA, and GHRKO mice treated (n = 10) or not (n = 10) with PMA were used. All were 6-month-old female mice. After the last PMA injection, the ovaries were collected for gene expression analysis. Expression of Amh, Gdf9, and Bmp15 was higher in GHRKO than N mice (P < 0.05), but was not different between PMA-treated N mice (P > 0.10). Expression of Amh and Gdf9 was higher (P < 0.05) for GHRKO PMA-treated mice. In addition, we observed a higher expression of Socs3 (P < 0.001) in GHRKO than N mice and a tendency for increased expression of Foxo3a (P = 0.07). For GHRKO PMA-treated mice, Foxo3a mRNA expression was higher (P = 0.02) and a tendency for higher expression of Mtor (P = 0.06) and Socs3 (P = 0.10) in GHRKO PMA-treated mice was observed. To summarize, the present data further confirm the previous histological observations that GHRKO mice have an ovarian phenotype characteristic of younger mice indicated by higher expression of Amh, Gdf9, and Bmp15 mRNA. In addition, we have shown a higher expression of Socs3 in GHRKO mice and higher Foxo3a expression in PMA-treated GHRKO mice, suggesting a role for these mediators in the process of ovarian aging.
doi:10.1007/s11357-014-9701-9
PMCID: PMC4150892  PMID: 25099774
GHRKO; FOXO3a; AMH; Aging; Ovary
16.  PPARs in Calorie Restricted and Genetically Long-Lived Mice 
PPAR Research  2006;2007:28436.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptors superfamily. The three subtypes, PPARα, PPARγ, and PPARβ/δ, are expressed in multiple organs. These transcription factors regulate different physiological functions such as energy metabolism (including lipid and carbohydrate metabolism), insulin action, and immunity and inflammation, and apparently also act as important mediators of longevity and aging. Calorie restriction (CR) is the most effective intervention known to delay aging and increase lifespan. Calorie restriction affects the same physiological functions as PPARs. This review summarizes recent findings on the effects of CR and aging on the expression of PPARγ, α, and β/δ in mice and discusses possible involvement of PPARs in mediating the effects of murine longevity genes. The levels of PPARs change with age and CR appears to prevent these alterations which make “PPARs-CR-AGING” dependence of considerable interest.
doi:10.1155/2007/28436
PMCID: PMC1779582  PMID: 17389764
17.  Resistance to the Beneficial Metabolic Effects and Hepatic Antioxidant Defense Actions of Fibroblast Growth Factor 21 Treatment in Growth Hormone-Overexpressing Transgenic Mice 
Fibroblast growth factor 21 (FGF21) modulates a diverse range of biological functions, including glucose and lipid metabolism, adaptive starvation response, and energy homeostasis, but with limited mechanistic insight. FGF21 treatment has been shown to inhibit hepatic growth hormone (GH) intracellular signaling. To evaluate GH axis involvement in FGF21 actions, transgenic mice overexpressing bovine GH were used. Expectedly, in response to FGF21 treatment control littermates showed metabolic improvements whereas GH transgenic mice resisted most of the beneficial effects of FGF21, except an attenuation of the innate hyperinsulinemia. Since FGF21 is believed to exert its effects mostly at the transcriptional level, we analyzed and observed significant upregulation in expression of various genes involved in carbohydrate and lipid metabolism, energy homeostasis, and antioxidant defense in FGF21-treated controls, but not in GH transgenics. The resistance of GH transgenic mice to FGF21-induced changes underlines the necessity of normal GH signaling for the beneficial effects of FGF21.
doi:10.1155/2015/282375
PMCID: PMC4451995  PMID: 26089880
18.  Gene expression of key regulators of mitochondrial biogenesis is sex dependent in mice with growth hormone receptor deletion in liver 
Aging (Albany NY)  2015;7(3):195-204.
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.
PMCID: PMC4394730  PMID: 25855408
mitochondrial biogenesis; gene disruption; growth hormone receptor; knockout mice; tissue-specific gene disruption; sexual dimorphism
19.  Primordial follicle activation in the ovary of Ames dwarf mice 
Background
The insulin receptor substrate 1 (IRS1), phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt1), Forkhead Box O3a (FOXO3a) pathway is directly involved in aging and ovarian activation of follicle growth. Therefore, the aim of this work was to measure the expression of genes related to the ovarian pathway for activation of primordial follicles and FOXO3a protein phosphorylation between young and old female Ames dwarf (df/df) and normal (N) mice.
Methods
For this study ovaries from N (n = 10) and df/df (n = 10) female mice were collected at 5–6 months of age and at 21–22 months of age. For immunohistochemistry ovaries from 12 month-old and df/df mice were used.
Results
The expression of Irs1, Pi3k, Akt1, mammalian target of rapamycin (Mtor), suppressor of cytokine signaling −2 (Socs2), Socs3 was lower (P < 0.05) in older than younger N mice and not different (P > 0.05) between young and old df/df mice. The expression of Foxo3a was also lower (P < 0.05) in old than younger N and df/df mice and was higher (P < 0.05) in old df/df than N mice. Expression of Amh was lower (P < 0.05) in old than young N and df/df mice and was higher (P = 0.0009) in df/df than N mice. Imunnostaining for p-FOXO3 was lower in df/df than N mice (P < 0.001), although FOXO3 immunostaining was not different (P > 0.05) between df/df and N mice.
Conclusions
In sum, the present study indicates that lower expression of Irs1, Socs2, Socs3, Akt1, Pi3k, Mtor and Foxo3a mRNA in the ovaries of older mice of both genotypes is associated to a reduced ovarian activity revealed by lower expression of Amh mRNA. At the same time, ovaries of old df/df mice maintained higher expression of Foxo3a mRNA, which was associated to higher ovarian activity. We have shown that df/df females have a lower level of p-FOXO3 in oocytes from primordial/primary follicles, an important activator of follicular growth. Therefore, this study strongly indicates that Prop1df mutation causes delayed ovarian aging.
doi:10.1186/s13048-014-0120-4
PMCID: PMC4354747  PMID: 25543533
Ames dwarf; Growth hormone; Ovaries; FOXO3a
20.  PIOGLITAZONE DOES NOT IMPROVE INSULIN SIGNALING IN MICE WITH GROWTH HORMONE OVER-EXPRESSION 
The Journal of endocrinology  2013;219(2):109-117.
Type 2 diabetes and obesity are very serious health problems in both developed and developing countries. Increased level of growth hormone (GH) is known to promote insulin resistance. Transgenic (Tg) mice over-expressing bovine GH are short-living and characterized, among others, by hyperinsulinemia and increased insulin resistance in comparison to normal (N) mice. Pioglitazone (PIO) is a member of the thiazolidinediones – group of insulin-sensitizing drugs which are selective agonists of peroxisome proliferator-activated receptor gamma (PPARγ). The aim of the study was to analyze the effects of PIO on the insulin signaling pathway in Tg and N mice. Plasma levels of insulin and glucose as well as hepatic levels of proteins involved in insulin signaling were analyzed by ELISA or western blot methods. Treatment with PIO decreased plasma level of glucose in N mice only. Similarly, PIO increased insulin sensitivity (expressed as the Relative Insulin Sensitivity Index; RISI) only in N mice. In the liver, PIO decreased the phosphorylation of IRS1 at a serine residue (Ser307-pS-IRS1), that inhibits insulin action, and had a tendency to increase tyrosine phosphorylation of IRS2 (Tyr-pY-IRS2) only in N mice but did not affect either of these parameters in Tg mice. Levels of total and phosphorylated mTOR were increased in Tg mice. Moreover, the AKT2 level was decreased by PIO in N mice only. In conclusion, the lack of improvement of insulin sensitivity in insulin-resistant Tg mice during PIO treatment suggests that chronically elevated GH level can inhibit the beneficial effects of PIO on insulin signaling.
doi:10.1530/JOE-13-0124
PMCID: PMC3811004  PMID: 23946430
pioglitazone; insulin signaling; growth hormone; transgenic mice
21.  Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice 
Aging (Albany NY)  2014;6(7):575-586.
The aging process is associated with the development of several chronic diseases. White adipose tissue (WAT) may play a central role in age-related disease onset and progression due to declines in adipogenesis with advancing age. Recent reports indicate that the accumulation of senescent progenitor cells may be involved in age-related WAT dysfunction. Growth hormone (GH) action has profound effects on adiposity and metabolism and is known to influence lifespan. In the present study we tested the hypothesis that GH activity would predict age-related WAT dysfunction and accumulation of senescent cells. We found that long-lived GH-deficient and -resistant mice have reduced age-related lipid redistribution. Primary preadipocytes from GH-resistant mice also were found to have greater differentiation capacity at 20 months of age when compared to controls. GH activity was also found to be positively associated with senescent cell accumulation in WAT. Our results demonstrate an association between GH activity, age-related WAT dysfunction, and WAT senescent cell accumulation in mice. Further studies are needed to determine if GH is directly inducing cellular senescence in WAT or if GH actions on other target organs or alternative downstream alterations in insulin-like growth factor-1, insulin or glucose levels are responsible.
PMCID: PMC4153624  PMID: 25063774
adipose tissue; aging; cellular senescence; growth hormone
22.  Decreased Levels of Proapoptotic Factors and Increased Key Regulators of Mitochondrial Biogenesis Constitute New Potential Beneficial Features of Long-lived Growth Hormone Receptor Gene–Disrupted Mice 
Decreased somatotrophic signaling is among the most important mechanisms associated with extended longevity. Mice homozygous for the targeted disruption of the growth hormone (GH) receptor gene (GH receptor knockout; GHRKO) are obese and dwarf, are characterized by a reduced weight and body size, undetectable levels of GH receptor, high concentration of serum GH, and greatly reduced plasma levels of insulin and insulin-like growth factor-I, and are remarkably long lived. Recent results suggest new features of GHRKO mice that may positively affect longevity—decreased levels of proapoptotic factors and increased levels of key regulators of mitochondrial biogenesis. The alterations in levels of the proapoptotic factors and key regulators of mitochondrial biogenesis were not further improved by two other potential life-extending interventions—calorie restriction and visceral fat removal. This may attribute the primary role to GH resistance in the regulation of apoptosis and mitochondrial biogenesis in GHRKO mice in terms of increased life span.
doi:10.1093/gerona/gls231
PMCID: PMC3708518  PMID: 23197187
Aging; Longevity; Dwarf mice; Apoptosis; Mitochondrial biogenesis; GHRKO mice; Calorie restriction; Visceral fat removal.
23.  Upregulation of the Angiotensin-Converting Enzyme 2/Angiotensin-(1-7)/Mas Receptor Axis in the Heart and the Kidney of Growth Hormone Receptor knock-out Mice 
Objective
Growth hormone (GH) resistance leads to enhanced insulin sensitivity, decreased systolic blood pressure and increased lifespan. The aim of this study was to determine if there is a shift in the balance of the renin-angiotensin system (RAS) towards the ACE2/Ang-(1-7)/Mas receptor axis in the heart and the kidney of a model of GH resistance and retarded aging, the GH receptor knockout (GHR−/−) mouse.
Design
RAS components were evaluated in the heart and the kidney of GHR−/− and control mice by immunohistochemistry and western blotting (n=12 for both groups).
Results
The immunostaining of Ang-(1-7) was increased in both the heart and the kidney of GHR−/− mice. These changes were concomitant with an increased immunostaining of the Mas receptor and ACE2 in both tissues. The immunostaining of AT1 receptor was reduced in heart and kidney of GHR−/− mice while that of AT2 receptor was increased in the heart and unaltered in the kidney. Ang II, ACE and angiotensinogen levels remained unaltered in the heart and the kidney of GH resistant mice. These results were confirmed by Western Blotting and correlated with a significant increase in the abundance of the endothelial nitric oxide synthase in both tissues.
Conclusions
The shift within the RAS towards an exacerbation of the ACE2/Ang-(1-7)/Mas receptor axis observed in GHR−/− mice could be related to a protective role in cardiac and renal function; and thus, possibly contribute to the decreased incidence of cardiovascular diseases displayed by this animal model of longevity.
doi:10.1016/j.ghir.2012.08.003
PMCID: PMC3698955  PMID: 22947377
Angiotensin-(1-7); AT1 receptor; Mas receptor; Growth hormone; Renin-angiotensin system

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