Effects Of Growth Hormone Research Articles

Effect of growth hormone therapy on Taiwanese children with growth hormone deficiency

Human growth hormone (GH) has been successfully used in children with GH deficiency (GHD). However, there are few published data on the effect of GH in Taiwanese children with GHD. We performed a retrospective cohort study to identify factors influencing the effect of GH therapy on ethnic Chinese children with GHD in Taiwan. Idiopathic GHD can be classified into isolated GHD (IGHD) and multiple pituitary hormone deficiency (MPHD). The study looked at the effect of GH on the auxological, biochemical, and imaging parameters of 51 patients (13 girls and 38 boys) in three different diagnostic groups: MPHD (n = 12), IGHD (n = 8), and transient GHD (TGHD; n = 31). TGHD is defined as a GH peak >10 μg/L in re-evaluation by two GH stimulation tests approximately 6 months after discontinuation of GH therapy. The height velocity for first-year GH therapy was 7.61 ± 1.46, 8.14 ± 1.92, and 9.99 ± 2.75 cm/y in the TGHD, IGHD, and MPHD groups, respectively. After post hoc comparison, the MPHD group had a significantly accelerated height velocity in the first year compared to the TGHD group. Correlation analysis showed that a change in height standard deviation score (SDS) in the first year had a significant negative correlation with the following variables: peak GH (r = -0.52, p < 0.001), pretreatment height SDS (r = -0.49, p < 0.001), and height-target height (Ht-TH) SDS (r = -0.49, p < 0.001). Change in height SDS in the first 2 years had a significantly negative correlation with peak GH (r = -0.51, p < 0.001), insulin-like growth factor-1 SDS (r = -0.35, p = 0.022), height SDS (r = -0.60, p < 0.001), difference between bone age and chronological age (r = -0.46, p = 0.001), and Ht-TH SDS (r = -0.50, p = 0.001). After using multiple linear regression, the pretreatment GH peak value was found to be significantly associated with height increments after 1 year of GH treatment (B = -0.07, p = 0.014). The administration of GH to children with GHD results in a pronounced acceleration in linear growth during the first year of treatment, especially in those with MPHD. The diagnosis of GHD requires comprehensive auxological, biochemical, and brain magnetic resonance imaging assessment. We also suggest that patients with GHD, specifically IGHD, must undergo a re-evaluation of GH secretion after completion of GH therapy.

Successful Treatment of Idiopathic Intracranial Hypertension (IIH) with Octreotide (P03.229)

Objective: To document a case of successful treatment of Ideopathic Intracranial Hypertension(IIH) with octreotide. Background Growth hormone mediated hyper secretion of CSF is the most accepted mechanism for IIH. Data from 57,968 children in the Pfizer International Growth Study database showed that IIH was one of the major side effects (80%) of GH. Octreotide, a somatostatin analogue, inhibits pituitary growth hormone(GH)secretion, and antagonizes GH and insulin like growth factor (IGF) action by blocking GH receptors. Design/Methods: A 39 year-old, obese female presented with headaches, intermittent visual blurring, and floaters for two years. Her examination was unremarkable except for papilloedema on fundoscopic exam. Computerized perimetry revealed marked impairment in the bilateral nasal fields. Brain MRI was normal, MR venogram showed hypoplastic left transverse venous sinus. The cerebrospinal fluid pressure was 30 cm of water, with a pulsatile CSF column. After initial use of diuretics being ineffective, lumbar punctures were recommended, but patient was not compliant to it. Results: Treatment with subcutaneous octreotide resulted in significant improvement of headaches, and normalization of visual fields and papilloedema. She tolerated the treatment well, except for formation of gallstones, for which treatment was stopped at around 9 months. However she continues to have persistent normalization of the vision and normal computerized perimetry after one and half year in follow up. Conclusions: Somatostatin receptors (SSTR I-5) are found in the choroid plexus, arachnoid granulations, and retina, which mediate the antisecretory and antiproliferative effects of somatostatin, which could be responsible for decreasing the intracranial pressure in IIH. Panagopoulos et al. treated 26 IIH patients with Octreotide for 6-8 months. Majority showed improvement of headache, visual symptoms, papilloedema and significant reduction of CSF pressure, which was persistent in follow up for three years. Further studies are warranted for its potential use in the treatment of IIH. Disclosure: Dr. Vyas has nothing to disclose. Dr. Phadke has received personal compensation for activities with Teva Neurosciences, Berlex and Glaxo Smith Kline as a speaker.

Pharmacodynamic Modeling of the Effects of Lanreotide Autogel on Growth Hormone and Insulin‐Like Growth Factor 1

Acromegaly arises from excessive levels of growth hormone (GH), many of whose effects are mediated by stimulation of secretion of insulin-like growth factor 1 (IGF-1). Synthetic somatostatin analogues inhibit GH secretion. The objective of the study was to develop a population pharmacodynamic model describing the relationship between serum concentrations of lanreotide (C(P)) and its GH and IGF-1 effects in patients with acromegaly receiving lanreotide Autogel (LA) at doses of 60, 90, or 120 mg by deep subcutaneous route every 28 days. Data were analyzed from 104 patients. The GH and IGF-1 profiles were fit simultaneously using the population approach with NONMEM. The GH vs C(P) and the IGF-1 vs GH relationships were described using inhibitory I(max) and E(max) models, respectively. Results indicated that lanreotide cannot abolish GH completely. C(P) levels of 3.4 ng/mL are required to achieve percentages of hormonal control (GH and IGF-1) of 21% and 36% in not treated and previously treated patients. If the focus is only GH, a C(P) of 3.4 ng/mL corresponds to 33% and 56% controlling rates. Simulations showed that there is a possible clinical benefit if the highest dose of 120 mg LA is administered to patients who are not well controlled by lower doses of LA.

Insulin-like growth factor 1

To summarize the recent evidence that insulin-like growth factor 1 (IGF1) mediates growth effects of multiple trophic factors and discuss clinical relevance. Recent reviews and original reports indicate benefits of growth hormone (GH) and long-acting glucagon-like peptide 2 (GLP2) analogs in short bowel syndrome and Crohn's disease. This review highlights the evidence that biomarkers of sustained small intestinal growth or mucosal healing and evaluation of intestinal epithelial stem cell biomarkers may improve clinical measures of intestinal growth or response to trophic hormones. Compelling evidence that IGF1 mediates growth effects of GH and GLP2 on intestine or linear growth in preclinical models of resection or Crohn's disease is presented, along with a concept that these hormones or IGF1 may enhance sustained growth if given early after bowel resection. Evidence that suppressor of cytokine signaling protein induction by GH or GLP2 in normal or inflamed intestine may limit IGF1-induced growth, but protect against risk of dysplasia or fibrosis, is reviewed. Whether IGF1 receptor mediates IGF1 action and potential roles of insulin receptors are addressed. IGF1 has a central role in mediating trophic hormone action in small intestine. Better understanding of benefits and risks of IGF1, receptors that mediate IGF1 action, and factors that limit undesirable growth are needed.

Enhanced oxidative stress in GH-transgenic rat and acromegaly in humans

BackgroundExcessive oxidative stress plays a causal role in various diseases such as diabetes, hypertension, atherosclerosis, and heart failure. Acromegaly is a pathological condition associated with excess growth hormone (GH) and insulin-like growth factor-I (IGF-I) and a high prevalence of diabetes, hypertension, atherosclerosis, and heart failure; resulting in premature death. We hypothesized that these conditions may be associated with increased oxidative stress. Objective and methodsWe explored the oxidative stress levels in the serum and tissues of GH-transgenic rats as an animal model for acromegaly. We also measured the oxidative stress levels in the serum of patients with acromegaly and age-, sex-, and BMI-matched control subjects. We examined the effects of GH and IGF-I on reactive oxygen species (ROS) production in C2C12 myocytes. ResultsThe levels of an oxidative stress marker, serum thiobarbituric acid reactive substances (TBARS) were increased in the GH-transgenic rats. Further, tissue oxidative stress damage was enhanced in the cardiomyocytes and vascular smooth muscle cells in the aorta of the GH-transgenic rats. In addition, serum TBARS levels and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were increased in acromegaly in humans. IGF-I but not GH induced ROS production in C2C12 myocytes in vitro. ConclusionsThese data indicate that the increased levels of IGF-I are associated with enhanced oxidative stress in rats and humans. In addition, increased ROS may play an important role in the complications and premature death in acromegaly.

Dynamic, Sex-Differential STAT5 and BCL6 Binding to Sex-Biased, Growth Hormone-Regulated Genes in Adult Mouse Liver

Sex-dependent pituitary growth hormone (GH) secretory patterns determine the sex-biased expression of >1,000 genes in mouse and rat liver, affecting lipid and drug metabolism, inflammation, and disease. A fundamental biological question is how robust differential expression can be achieved for hundreds of sex-biased genes simply based on the GH input signal pattern: pulsatile GH stimulation in males versus near-continuous GH exposure in females. STAT5 is an essential transcriptional mediator of the sex-dependent effects of GH in the liver, but the mechanisms that underlie its sex-dependent actions are obscure. Here we elucidate the dynamic, sex-dependent binding of STAT5 and the GH/STAT5-regulated repressor BCL6 to mouse liver chromatin genome wide, revealing a counteractive interplay between these two regulators of sex differences in liver gene expression. Our findings establish a close correlation between sex-dependent STAT5 binding and sex-biased target gene expression. Moreover, sex-dependent STAT5 binding correlated positively with sex-biased DNase hypersensitivity and H3-K4me1 and H3-K4me3 (activating) marks, correlated negatively with sex-biased H3-K27me3 (repressive) marks, and was associated with sex-differentially enriched motifs for HNF6/CDP factors. Importantly, BCL6 binding was preferentially associated with repression of female-biased STAT5 targets in male liver. Furthermore, BCL6 and STAT5 common targets but not BCL6 unique targets showed strong enrichment for lipid and drug metabolism. These findings provide a comprehensive, genome-wide view of the mechanisms whereby these two GH-regulated transcription factors establish and maintain sex differences affecting liver physiology and disease. The approaches used here to characterize sex-dependent STAT5 and BCL6 binding can be applied to other condition-specific regulatory factors and binding sites and their interplay with cooperative chromatin binding factors.

Genetic evidence that thyroid hormone is indispensable for prepubertal insulin-like growth factor–I expression and bone acquisition in mice

Understanding how bone growth is regulated by hormonal and mechanical factors during early growth periods is important for optimizing the attainment of peak bone mass to prevent or postpone the occurrence of fragility fractures later in life. Using genetic mouse models that are deficient in thyroid hormone (TH) (Tshr(-/-) and Duox2(-/-)), growth hormone (GH) (Ghrhr(lit/lit)), or both (Tshr(-/-); Ghrhr(lit/lit)), we demonstrate that there is an important period prior to puberty when the effects of GH are surprisingly small and TH plays a critical role in the regulation of skeletal growth. Daily administration of T3/T4 during days 5 to 14, the time when serum levels of T3 increase rapidly in mice, rescued the skeletal deficit in TH-deficient mice but not in mice lacking both TH and GH. However, treatment of double-mutant mice with both GH and T3/T4 rescued the bone density deficit. Increased body fat in the TH-deficient as well as TH/GH double-mutant mice was rescued by T3/T4 treatment during days 5 to 14. In vitro studies in osteoblasts revealed that T3 in the presence of TH receptor (TR) α1 bound to a TH response element in intron 1 of the IGF-I gene to stimulate transcription. In vivo studies using TRα and TRβ knockout mice revealed evidence for differential regulation of insulin-like growth factor (IGF)-I expression by the two receptors. Furthermore, blockade of IGF-I action partially inhibited the biological effects of TH, thus suggesting that both IGF-I-dependent and IGF-I-independent mechanisms contribute to TH effects on prepubertal bone acquisition.

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

Suppressor of Cytokine Signaling-2 (SOCS2) is a negative regulator of growth hormone (GH) signaling and bone growth via inhibition of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. This has been classically demonstrated by the overgrowth phenotype of SOCS2(-/-) mice, which has normal systemic insulin-like growth factor 1 (IGF-1) levels. The local effects of GH on bone growth are equivocal, and therefore this study aimed to understand better the SOCS2 signaling mechanisms mediating the local actions of GH on epiphyseal chondrocytes and bone growth. SOCS2, in contrast to SOCS1 and SOCS3 expression, was increased in cultured chondrocytes after GH challenge. Gain- and loss-of-function studies indicated that GH-stimulated chondrocyte STATs-1, -3, and -5 phosphorylation was increased in SOCS2(-/-) chondrocytes but not in cells overexpressing SOCS2. This increased chondrocyte STAT signaling in the absence of SOCS2 is likely to explain the observed GH stimulation of longitudinal growth of cultured SOCS2(-/-) embryonic metatarsals and the proliferation of chondrocytes within. Consistent with this metatarsal data, bone growth rates, growth plate widths, and chondrocyte proliferation were all increased in SOCS2(-/-) 6-week-old mice as was the number of phosphorylated STAT-5-positive hypertrophic chondrocytes. The SOCS2(-/-) mouse represents a valid model for studying the local effects of GH on bone growth.

Growth Hormone Receptors in the Brain and their Potential as Therapeutic Targets in Central Nervous System Disorders

Effects that growth hormone (GH) may exert on brain function have received attention among many researchers over the past two decades. In patients with impaired pituitary production of this hormone replacement therapies have been demonstrated not only to compensate for GH effects in peripheral organs but also to improve several behaviors related to the brain. For instance, available data suggests that subjects treated with GH have experienced significant improvements in concentration, memory, depression, anxiety and fatigue. Also, pituitary-ectomized male rats showing decreased ability in tasks related to learning and memory are seen to improve their performance in these items following GH replacement. The mechanism underlying these beneficial effects of GH has been the subject of studies in many laboratories. An important aspect in this regard is the discovery of specific receptors in various brain regions related to the functional anatomy of several behaviors affected by the hormone. The aim with this article is to review current knowledge on GH receptors in the brain and discuss possible mechanism for the action of the hormone in its ability to affects brain function.

Targeted Loss of GHR Signaling in Mouse Skeletal Muscle Protects Against High-Fat Diet–Induced Metabolic Deterioration

Growth hormone (GH) exerts diverse tissue-specific metabolic effects that are not revealed by global alteration of GH action. To study the direct metabolic effects of GH in the muscle, we specifically inactivated the growth hormone receptor (ghr) gene in postnatal mouse skeletal muscle using the Cre/loxP system (mGHRKO model). The metabolic state of the mGHRKO mice was characterized under lean and obese states. High-fat diet feeding in the mGHRKO mice was associated with reduced adiposity, improved insulin sensitivity, lower systemic inflammation, decreased muscle and hepatic triglyceride content, and greater energy expenditure compared with control mice. The obese mGHRKO mice also had an increased respiratory exchange ratio, suggesting increased carbohydrate utilization. GH-regulated suppressor of cytokine signaling-2 (socs2) expression was decreased in obese mGHRKO mice. Interestingly, muscles of both lean and obese mGHRKO mice demonstrated a higher interleukin-15 and lower myostatin expression relative to controls, indicating a possible mechanism whereby GHR signaling in muscle could affect liver and adipose tissue function. Thus, our study implicates skeletal muscle GHR signaling in mediating insulin resistance in obesity and, more importantly, reveals a novel role of muscle GHR signaling in facilitating cross-talk between muscle and other metabolic tissues.

Growth Hormone Promotes Hair Cell Regeneration in the Zebrafish (Danio rerio) Inner Ear following Acoustic Trauma

BackgroundPrevious microarray analysis showed that growth hormone (GH) was significantly upregulated following acoustic trauma in the zebrafish (Danio rerio) ear suggesting that GH may play an important role in the process of auditory hair cell regeneration. Our objective was to examine the effects of exogenous and endogenous GH on zebrafish inner ear epithelia following acoustic trauma.Methodology/Principal FindingsWe induced auditory hair cell damage by exposing zebrafish to acoustic overstimulation. Fish were then injected intraperitoneally with either carp GH or buffer, and placed in a recovery tank for either one or two days. Phalloidin-, bromodeoxyuridine (BrdU)-, and TUNEL-labeling were used to examine hair cell densities, cell proliferation, and apoptosis, respectively. Two days post-trauma, saccular hair cell densities in GH-treated fish were similar to that of baseline controls, whereas buffer-injected fish showed significantly reduced densities of hair cell bundles. Cell proliferation was greater and apoptosis reduced in the saccules, lagenae, and utricles of GH-treated fish one day following trauma compared to controls. Fluorescent in situ hybridization (FISH) was used to examine the localization of GH mRNA in the zebrafish ear. At one day post-trauma, GH mRNA expression appeared to be localized perinuclearly around erythrocytes in the blood vessels of the inner ear epithelia. In order to examine the effects of endogenous GH on the process of cell proliferation in the ear, a GH antagonist was injected into zebrafish immediately following acoustic trauma, resulting in significantly decreased cell proliferation one day post-trauma in all three zebrafish inner ear end organs.Conclusions/SignificanceOur results show that exogenous GH promotes post-trauma auditory hair cell regeneration in the zebrafish ear through stimulating proliferation and suppressing apoptosis, and that endogenous GH signals are present in the zebrafish ear during the process of auditory hair cell regeneration.

Local expression and distribution of growth hormone and growth hormone receptor in the chicken ovary: Effects of GH on steroidogenesis in cultured follicular granulosa cells

Preovulatory follicular development (PFD) is mainly regulated by gonadotropins (FSH, LH) and steroids, although other intraovarian factors are also involved. We analyzed the local expression of growth hormone (GH) in the hen ovary and the role that this hormone may play on the regulation of steroidogenesis in granulosa cells (GCs). Ovarian follicles from sexually mature hens were studied at different developmental stages. Both GH mRNA (by in situ hybridization) and protein (by immunohistochemistry) were expressed mainly in the GCs, and to a lesser extent in the theca cells of the follicular wall. Sequence of a GH cDNA 690-bp fragment obtained from the follicular wall was identical to that obtained from the pituitary. The growth hormone receptor (GHR) mRNA was also expressed in the follicles. Nine GH variants were observed by SDS–PAGE and Western blotting, but the main isoform showed a MW of 17 kDa, at all developmental stages. Addition of GH (0.1, 1, 10 nM) stimulated the synthesis of progesterone (P4) in primary GCs cultures in a dose-dependent manner (1.5, 2.9, 5.4 times, respectively). GH also stimulated the expression of cholesterol side-chain cleavage enzyme (cytochrome P450scc) mRNA, a rate-limiting enzyme during P4 synthesis (2.9, 4.6, 4.9 times, respectively), whereas the synthesis of 3β-hydroxysteroid dehydrogenase (3β-HSD) mRNA (a constitutive enzyme) was not changed. Both GH and GHR were co-expressed in GCs cultures. The locally expressed GH present in concentrated (4×, 6×, 8×) conditioned media obtained from ovarian GC cultures stimulated P4 production (1.2, 2.2, 4.4 times, respectively) in additional fresh cultured GCs, and this effect disappeared when the conditioned media were treated with antiserum against GH. These data suggest that locally produced GH may modulate follicular development through autocrine/paracrine effects in the chicken ovary.

An Assessment of Androgenic/Anti-androgenic Effects of GH Transgenic Carp by Hershberger Assay

Objective To evaluate the androgenic and anti-androgenic effects of GH (growth hormone) transgenic carp in male rats. Methods Hershberger assay was carried out in castrated male SD rats aged 4-5 weeks. Testosterone propionate (TP) (0.4 mg/kg BW) was administrated for a positive control, GH transgenic carp (3.0 g/kg BW)+TP (0.4 mg/kg BW), parental carp (3.0 g/kg BW) + TP (0.4 mg/kg BW), and flutamide (Flu) (3.0 g/kg BW) were used for negative controls, and vehicle was administered orally for a blank control. All groups were administrated for 10 consecutive days. At the end of the test, animals were anesthetized, then weights of accessory sex organ were measured. Serum testosterone (T), luteinizing hormone (LH), and Follicle-Stimulating Hormone (FSH) levels were detected. Results The weights ratios of the accessory sex organs and body weights showed no significant differences between the solvent control and the GH transgenic carp-treated groups. Serum concentrations of FSH, LH, and T of the rats treated with GH transgenic carp + TP showed no significant changes, compared with those treated with TP only. Conclusion GH transgenic carp does not have any androgenic agonist or antagonist properties in vivo screening tests.

Growth hormone treatment in adults with Prader-Willi syndrome: the Scandinavian study

Prader-Willi syndrome (PWS) is characterized by short stature, muscular hypotonia, cognitive dysfunction, and hyperphagia usually leading to severe obesity. Patients with PWS share similarities with growth hormone deficiency (GHD). Few studies have dealt with growth hormone (GH) treatment in PWS adults. The purpose of the Scandinavian study was to evaluate the effects of GH on body composition, lipid and glucose metabolism, physical performance and safety parameters in adults with PWS. Twenty-five women and 21 men with PWS were randomized to treatment with GH or placebo during 1year followed by 2years of open labeled GH treatment. At baseline 1/3 had normal BMI, six patients severe GHD, ten impaired glucose tolerance and seven diabetes. At 1year insulin-like growth factor I (IGF-I) SDS had increased by 1.51 (P<0.001) and body composition improved in the GH treated group. Visceral fat decreased by 22.9ml (P=0.004), abdominal subcutaneous fat by 70.9ml (P=0.003) and thigh fat by 21.3ml (P=0.013), whereas thigh muscle increased 6.0ml (P=0.005). Lean body mass increased 2.25kg (P=0.005), and total fat mass decreased 4.20kg (P<0.001). The positive effects on body composition were maintained after 2years of GH treatment. Peak expiratory flow increased by 12% (P<0.001) at 2years of GH treatment. Lipid and glucose metabolism were unchanged, however, three patients developed diabetes at 2years of GH treatment. In conclusion GH treatment had beneficial effects on the abnormal body composition without serious adverse events making it a logic treatment option in adults with PWS.

Identification of Novel GH-regulated Genes in C2C12 Cells

Growth hormone (GH) is the main regulator of longitudinal growth before puberty, and treatment with human recombinant (rh) GH can increase muscle strength. Nevertheless, molecular mechanisms responsible remain mostly unknown. Many physiological effects of GH require hormone-mediated changes in gene expression. In an attempt to gain insight into the mechanism of GH action in muscle cells we evaluated the effects of rhGH on gene expression profile in a murine skeletal muscle cell line C2C12. The objective of the work was to identify changes in gene expression in the murine skeletal muscle cell line C2C12 after rGH treatment using microarray assays. C2C12 murine skeletal muscle cell cultures were differentiated during 4 days. After 16 h growing in serum-free medium, C2C12 myotubes were stimulated during 6 h with 500 ng/ml rhGH. Four independent sets of experiments were performed to identify GH-regulated genes. Total RNA was isolated and subjected to analysis. To validate changes candidate genes were analyzed by real-time quantitative polymerase chain reaction. One hundred and fifty-four differentially expressed genes were identified; 90 upregulated and 64 downregulated. Many had not been previously identified as GH-responsive. Real-time PCR in biological replicates confirmed the effect of rGH on 15 genes: Cish, Serpina3g, Socs2, Bmp4, Tnfrsf11b, Rgs2, Tgfbr3, Ugdh, Npy1r, Gbp6, Tgfbi, Tgtp, Btc, Clec3b, and Bcl6. This study shows modifications in the gene expression profile of the C2C12 cell line after rhGH exposure. In vitro and gene function analysis revealed genes involved in skeletal and muscle system as well as cardiovascular system development and function.

Effect of growth hormone and melatonin on the brain: from molecular mechanisms to structural changes.

Aging of the brain causes important reductions in quality of life and has wide socio-economic consequences. An increase in oxidative stress, and the associated inflammation and apoptosis, could be responsible for the pathogenesis of aging associated brain lesions. Melatonin has neuroprotective effects, by limiting the negative effects of oxygen and nitrogen free radicals. Growth hormone (GH) might exert additional neuro-protective and or neurogenic effects on the brain. The molecular mechanisms of the protective effects of GH and melatonin on the aging brain have been investigated in young and old Wistar rats. A reduction in the total number of neurons in the hilus of the dentate gyrus was evident at 24months of age and was associated with a significant increase in inflammation markers as well as in pro-apoptotic parameters, confirming the role of apoptosis in its reduction. Melatonin treatment was able to enhance neurogenesis in old rats without modification of the total number of neurons, whereas GH treatment increased the total number of neurons without enhancing neurogenesis. Both GH and melatonin were able to reduce inflammation and apoptosis in the hippocampus. In conclusion, neuroprotective effects demonstrated by GH and melatonin in the hippocampus were exerted by decreasing inflammation and apoptosis.

Growth Hormone Induces Hepatic Production of Fibroblast Growth Factor 21 through a Mechanism Dependent on Lipolysis in Adipocytes

Fibroblast growth factor (FGF) 21 and growth hormone (GH) are metabolic hormones that play important roles in regulating glucose and lipid metabolism. Both hormones are induced in response to fasting and exert their actions on adipocytes to regulate lipolysis. However, the molecular interaction between these two hormones remains unclear. Here we demonstrate the existence of a feedback loop between GH and FGF21 on the regulation of lipolysis in adipocytes. A single bolus injection of GH into C57 mice acutely increases both mRNA and protein expression of FGF21 in the liver, thereby leading to a marked elevation of serum FGF21 concentrations. Such a stimulatory effect of GH on hepatic FGF21 production is abrogated by pretreatment of mice with the lipolysis inhibitor niacin. Direct incubation of either liver explants or human HepG2 hepatocytes with GH has no effect on FGF21 expression. On the other hand, FGF21 production in HepG2 cells is significantly induced by incubation with the conditioned medium harvested from GH-treated adipose tissue explants, which contains high concentrations of free fatty acids (FFA). Further analysis shows that FFA released by GH-induced lipolysis stimulates hepatic FGF21 expression by activation of the transcription factor PPARα. In FGF21-null mice, both the magnitude and duration of GH-induced lipolysis are significantly higher than those in their wild type littermates. Taken together, these findings suggest that GH-induced hepatic FGF21 production is mediated by FFA released from adipose tissues, and elevated FGF21 in turn acts as a negative feedback signal to terminate GH-stimulated lipolysis in adipocytes.

Growth hormone doping: a review

The use of growth hormone (GH) as a performance enhancing substance was first promoted in lay publications, long before scientists fully acknowledged its benefits. It is thought athletes currently use GH to enhance their athletic performance and to accelerate the healing of sporting injuries. Over recent years, a number of high profile athletes have admitted to using GH. To date, there is only limited and weak evidence for its beneficial effects on performance. Nevertheless the “hype” around its effectiveness and the lack of a foolproof detection methodology that will detect its abuse longer than 24 hours after the last injection has encouraged its widespread use. This article reviews the current evidence of the ergogenic effects of GH along with the risks associated with its use. The review also examines methodologies, both currently available and in development for detecting its abuse.

CDNA cloning of two types of growth hormone receptor in torafugu Takifugu rubripes: tissue distribution is possibly correlated to lipid accumulation patterns

Growth hormone (GH) is an important hormone with primary roles in growth, lipid metabolism, osmoregulation, and immunity in fish, via the growth hormone receptor (GHR). We have cloned cDNAs from the torafugu pufferfish Takifugu rubripes encoding two distinct GHRs. Phylogenetic analysis of these GHRs together with their counterparts from other fish led to the identification of 1914- and 1695-bp cDNAs for torafugu GHR1 and GHR2, respectively. The deduced amino acid sequences of GHR1 and GHR2 showed 34% identity and, in comparison to torafugu GHR1, torafugu GHR2 lacked three extracellular cysteine and five intracellular tyrosine residues, suggesting that the two torafugu GHRs have different functions in GH/GHR signaling. Real-time PCR revealed that the transcript abundance of torafugu GHR1 and GHR2 tended to be high in fast muscle, slow muscle, and liver. Notably, the relative mRNA level of torafugu GHR1 was significantly higher in fast muscle, in comparison to the GHR1s from other fish reported to date where the highest relative mRNA levels have been found in the liver. Taken together with the well-known lipolytic effects of GH on fish liver, these expression patterns of torafugu GHRs suggest its liver-specific lipid accumulation.

Is growth hormone expression correlated with variation in growth rate along a latitudinal gradient in Rana temporaria ?

In ectotherms, decreasing season length and lower temperature towards higher latitudes often favour higher growth and developmental rates. However, the underlying physiological mechanisms and particularly the hormonal correlates of clinal variation remain unexplored. The growth hormone (GH) plays a crucial role in growth of all vertebrates and high expression of GH is associated with rapid growth in many species. We tested the hypothesis that GH expression is correlated with a latitudinal gradient in growth in Scandinavian Rana temporaria tadpoles. Using quantitative polymerase chain reaction, we measured GH and growth hormone receptor (GHR) expression at two time points from laboratory-raised tadpoles originating from eight populations collected along the latitudinal gradient. To explore latitudinal differences in stress-induced changes in GH expression, we also compared GH expression in tadpoles raised with and without predators. In accordance with previous studies we found a clear latitudinal gradient in growth. There were no latitudinal effects, or predator-induced effects on GH or GHR expression. However, there was some indication for among-population variation in GH expression. The lack of a latitudinal pattern in GH and GHR expression may be due to that the growth promoting effects of GH is dependent on other factors including insulin-like growth factor-I (IGF), IGF-binding proteins or prolactin. Further studies on these factors may provide insight on the proximal mechanisms of differences in growth in R. temporaria tadpoles.