Infusion Of Growth Hormone Research Articles

Uterine infusion strategies for infertile patients with recurrent implantation failure: a systematic review and network meta-analysis

BackgroundIntra-uterine infusion treatments were reported to be beneficial to embryo implantation and pregnancy outcomes, and considered as potential therapies for infertile patients with recurrent implantation failure (RIF). Nevertheless, their efficiencies were controversial and there lack of consensus on which intrauterine treatment is the most effective.MethodsAll prospective trials (in Chinese or English) were searched in Databases PubMed, Cochrane, Web of Science, and CNKI from July 2013 to July 2023. We included studies that investigated various uterine infusions, including chorionic gonadotropin, granulocyte colony-stimulating factor, monocytes, platelet-rich plasma, etc. during IVF treatment and reported subsequent pregnancy outcomes.ResultsWe finally included 56 researches, including 40 randomized controlled trials, 14 non-randomized controlled trials, and 3 prospective cohort studies. This study included a total of 11 uterine perfusion methods: Placebo, Human Chorionic Gonadotropin (HCG), Granulocyte Colony-Stimulating Factor (G-CSF), platelet-rich plasma (PRP), Peripheral Blood Mononuclear Cell (PBMC), Growth hormone (GH), dexamethasone (DEX), Embryo culture supernatant (ESC), PRP combined with G-CSF (PRP + G-CSF), RPR combined with subcutaneous injection of G-CSF (RPR + G-CSFsc), G-CSF combined with subcutaneous injection of AXaIU (G-CSF + AXaIUsc). Intrauterine infusion of HCG, PBMC, G-CSF, and PRP significantly improves pregnancy outcomes in patients with repeated implantation failure compared with blank controls or placebo, and PRP improved the clinical pregnancy and live birth most. GH and ESC infusion might improve the pregnancy outcomes, but uterine infusion of DEX was shown with high miscarriage. The combination therapy did not show a significant advantage over the mono-therapy.ConclusionsIntrauterine infusion of HCG, PBMC, G-CSF, and PRP are promising strategies for improving pregnancy outcomes for infertile patients with recurrent implantation failure. Among these treatments, PRP may be the best. More researches are required to explore the effect of drug combinations and less commonly used drugs as well.Trial registrationOur study was registered in PROSPERO and the ID was CRD42023467188.

Sparse Deconvolution of Pulsatile Growth Hormone Secretion in Adolescents.

Growth hormone (GH) is secreted by cells in the anterior pituitary on two time scales: discrete pulses over minutes that occur within a 24-hr pattern. Secretion reflects the balance of stimulatory and inhibitory inputs from the hypothalamus and is influenced by gonadal steroids, stress, nutrition, and sleep/wake states. We propose a novel approach for the analysis of GH data and use this approach to quantify (i) the timing, amplitude and the number of GH pulses and (ii) GH infusion, clearance and basal secretion (i.e., time invariant) rates, using serum GH sampled every 10 minutes during an 8-hour sleep study in 18 adolescents. In our method, we approximate hormonal secretory events by deconvolving GH data via a two-step coordinate descent approach. The first step utilizes a sparse-recovery approach to estimate the timing and amplitude of GH secretory events. The second step estimates physiological parameters. Our method identifies the timing and amplitude of GH pulses and system parameters from experimental and simulated data, with a median R2 of 0.93, among experimental data. Recovering GH pulses and model parameters using this approach may improve the quantification of GH parameters under different physiological and pathological conditions and the design and monitoring of interventions.

Effect of growth hormone on thin endometrium via intrauterine infusion.

BackgroundA thin endometrium has become a common reason for the repeated implantation failure. Growth hormone (GH) can regulate the proliferation and metabolism of endometrial cells. The aim of this study was to explore the effect of GH on thin endometrium.MethodsA total of 48 female Sprague-Dawley (SD) rats were randomly assigned to the following 4 groups with 12 rats in each group: blank control, model, subcutaneous, and GH groups. The blank control group was untreated and maintained in a routine manner. The model, subcutaneous, and GH groups were intrauterine perfused with 95% ethanol during estrus. After 6–8 h, the model group was intrauterine perfused with 0.2 mL normal saline, the subcutaneous group received subcutaneous injection of 0.12 mg/kg GH dissolved in 0.2 mL normal saline, and the GH group was intrauterine perfused with 0.12 mg/kg GH dissolved in 0.2 mL normal saline. Hematoxylin and eosin (HE) staining was used to examine the thickness of the endometrium. The expression of cytokeratin and vimentin was detected by western blotting and immunohistochemistry.ResultsThe intima thickness in the GH group and blank control group was increased compared with that in the model group (P<0.01). The intima thickness in the subcutaneous group was increased compared with that in the model group, but there was no significant difference. The expression of vimentin and cytokeratin was increased in the GH (P<0.01) and blank control (P<0.01) groups compared with that in the model group.ConclusionsIntrauterine perfusion of GH can promote the regeneration and repair of thin endometrium in rats. The therapeutic effect of uterine infusion of GH is better than that of subcutaneous injection of GH.

Feminization of Male Mouse Liver by Persistent Growth Hormone Stimulation: Activation of Sex-Biased Transcriptional Networks and Dynamic Changes in Chromatin States.

ABSTRACTSex-dependent pituitary growth hormone (GH) secretory profiles—pulsatile in males and persistent in females—regulate the sex-biased, STAT5-dependent expression of hundreds of genes in mouse liver, imparting sex differences in hepatic drug/lipid metabolism and disease risk. Here, we examine transcriptional and epigenetic changes induced by continuous GH infusion (cGH) in male mice, which rapidly feminizes the temporal profile of liver STAT5 activity. cGH repressed 86% of male-biased genes and induced 68% of female-biased genes within 4 days; however, several highly female-specific genes showed weak or no feminization, even after 14 days of cGH treatment. Female-biased genes already in an active chromatin state in male liver generally showed early cGH responses; genes in an inactive chromatin state often responded late. Early cGH-responsive genes included those encoding two GH/STAT5-regulated transcriptional repressors: male-biased BCL6, which was repressed, and female-specific CUX2, which was induced. Male-biased genes activated by STAT5 and/or repressed by CUX2 were enriched for early cGH repression. Female-biased BCL6 targets were enriched for early cGH derepression. Changes in sex-specific chromatin accessibility and histone modifications accompanied these cGH-induced sex-biased gene expression changes. Thus, the temporal, sex-biased gene responses to persistent GH stimulation are dictated by GH/STAT5-regulated transcription factors arranged in a hierarchical network and by the dynamics of changes in sex-biased epigenetic states.

Abstract 397: Chronic Infusion of Growth Hormone Releasing Hormone Prevents Heart Failure with Preserved Ejection Fraction Phenotype Development in Murine Cardiomyocytes by Reducing Myofilament Sensitivity to Calcium

Introduction: Heart failure with preserved ejection fraction (HFpEF) represents ~50% of heart failure cases and is characterized by impaired relaxation, ventricular stiffening and fibrosis. Growth hormone releasing hormone agonists (GHRH-A) reduce fibrosis in rat and swine models of ischemic myocardial injury. However, their effect on failing cardiomyocytes (CMs) is unknown. We hypothesized that activation of GHRH receptor signaling targets proteins associated with excitation-contraction coupling, reduces affinity of myofilaments for Ca 2+ and prevents the development of HFpEF. Methods: CD1 mice, implanted with mini-osmotic pump (Alzet) to deliver angiotensin-II (Ang-II) for 4 weeks, received daily injections of GHRH-A (MR-356; n=8) or vehicle (n=8). CMs were isolated and Ca 2+ and sarcomere length recorded. Expression and phosphorylation of Ca 2+ handling and sarcomeric proteins were assessed. Unmanipulated CD1 mice (n=7) acted as normal controls. Results: Ang-II-treated CMs exhibited reduced sarcomere length consistent with shorter cell length, indicating an inability to completely relax. These CMs also exhibited impaired contractility that correlated with reduced myosin binding protein C (cMyBPC) expression with no changes in phosphorylation. Response of [Ca 2+ ] transient amplitude to increasing pacing rate was depressed and Ca 2+ decay was delayed and associated with lower expression of SERCA2 and NCX1, increased SR Ca 2+ leak but no change in phospholamban phosphorylation (p-PLB) at Ser16. Slower sarcomere re-lengthening and reduced phospho-cTnI (p-cTnI) at Ser 23/24 were observed in HFpEF CMs. MR-356 treatment maintained resting sarcomere length as well as sarcomere shortening at control values, and completely abrogated Ang-II-induced delay in Ca 2+ decay and sarcomere relaxation. SR Ca 2+ leak was reduced. p-PLB was further enhanced by MR-356, and cMyBPC and p-cTnI were maintained at control levels. Conclusion: Our findings demonstrate that chronic administration of Ang-II mediates functional changes in CMs consistent with HFpEF and suggest that activation of the GHRH receptor signaling pathways desensitizes myofilaments and prevents HFpEF-associated alterations in Ca 2+ handling and dysfunctional CM relaxation.

Effects of sexually dimorphic growth hormone secretory patterns on arachidonic acid metabolizing enzymes in rodent heart

The arachidonic acid (AA) metabolizing enzymes are the potential therapeutic targets of cardiovascular diseases (CVDs). As sex differences have been shown in the risk and outcome of CVDs, we investigated the regulation of heart AA metabolizing enzymes (COXs, LOXs, and CYPs) by sex-dependent growth hormone (GH) secretory patterns. The pulsatile (masculine) GH secretion at a physiological concentration decreased CYP1A1 and CYP2J3 mRNA levels more efficiently in the H9c2 cells compared with the constant (feminine) GH secretion; however, CYP1B1 mRNA levels were higher following the pulsatile GH secretion. Sex differences in CYP1A1, CYP1B1, and CYP2J11 mRNA levels were observed in both the wild-type and GHR deficient mice. No sex differences in the mRNA levels of COXs, LOXs, or CYP2E1 were observed in the wild-type mice. The constant GH infusion induced heart CYP1A1 and CYP2J11, and decreased CYP1B1 in the male C57/B6 mice constantly infused with GH (0.4μg/h, 7days). The activity of rat Cyp2j3 promoter was inhibited by the STAT5B protein, but was activated by C/EBPα (CEBPA). Compared with the constant GH administration, the levels of the nuclear phosphorylated STAT5B protein and its binding to the rat Cyp2j3 promoter were higher following the pulsatile GH administration. The constant GH infusion decreased the binding of the nuclear phosphorylated STAT5B protein to the mouse Cyp2j11 promoter. The data suggest the sexually dimorphic transcription of heart AA metabolizing enzymes, which might alter the risk and outcome of CVDs. GHR-STAT5B signal transduction pathway may be involved in the sex difference in heart CYP2J levels.

Protein and glucose metabolic responses to hyperinsulinemia, hyperglycemia, and hyperaminoacidemia in obese men.

In insulin-resistant states, resistance of protein anabolism occurs concurrently with that of glucose, but can be compensated for by abundant amino acid (AA) provision. This effect and its mechanism were sought in obesity. Pancreatic clamps were performed in 8 lean and 11 obese men, following 5-h postabsorptive, 3-h infusions of octreotide, basal glucagon, and growth hormone, with clamped postprandial-level insulin, glucose, and AA. Whole-body [1-(13) C]-leucine and [3-(3) H]-glucose kinetics, skeletal muscle protein ((2) H5 -phenylalanine) fractional synthesis rates, and insulin signaling were determined. Clamp Δ insulin and Δ branched-chain AA did not differ; fasting glucagon and growth hormone were maintained. Glucose uptake was 20% less in obese concurrent with less Akt(Ser473) , but also less IRS-1(Ser636/639) phosphorylation. Stimulation of whole-body, myofibrillar, and sarcoplasmic protein synthesis was similar. Whole-body protein catabolism suppression tended to be less (P=0.06), resulting in lesser net balance (1.09 ± 0.07 vs. 1.31 ± 0.08 μmol [kg FFM(-1) ] min(-1) , P=0.048). Increments in muscle S6K1(Thr389) phosphorylation were less in the obese, but 4E-BP1(Ser65) did not differ. Hyperaminoacidemia with hyperinsulinemia stimulated protein synthesis (possibly via nutrient signaling) normally in obesity, but suppression of proteolysis may be compromised. Whether long-term high protein intakes could compensate for the insulin resistance of protein anabolism remains to be determined.

Erratum to: Infusion of growth hormone into the hippocampus induces molecular and behavioral responses in mice

Erratum to: Infusion of growth hormone into the hippocampus induces molecular and behavioral responses in mice

Infusion of growth hormone into the hippocampus induces molecular and behavioral responses in mice.

Growth hormone (GH) has been implicated in a variety of brain functions, including neural development, cognition, and neuroprotection. The biological effects of GH are known to rely on the binding of GH to the GH receptor (GHR), yet the resulting signals in the brain remain poorly understood. The present study investigated the effects of hippocampal infusions of recombinant GH and a GHR antagonist on the expression of immediate early genes (IEGs) and behavioral responses in mice. The infusions induced differential expression of Arc, Nr4a1, and Npas4 mRNAs among the IEGs. The infusions also elicited differential behavioral responses, such as varied levels of spontaneous locomotion, self-grooming, and frequency of access to the corner fields in the open-field test. Polynomial regression analyses and canonical discriminant analyses between gene expression and behavioral changes demonstrated that the expression level of Arc mRNA was strongly correlated with locomotor activity level (r = 0.71 and 0.92 on days 8 and 10, respectively) and that the correlation was completely discriminable between drugs (error rate = 0%). This analysis also revealed that a decrease in Npas4 mRNA was negatively correlated with the number of corner accesses (r = -0.63) and that this correlation was partially discriminable between drugs (error rate = 16.67%). Taken together, these results suggest that the GH-GHR complex modulates Arc and Npas4 signaling, which affects spontaneous locomotor and exploratory behaviors.

Circadian variation in the pharmacokinetics of steady state continuous subcutaneous infusion of growth hormone in adult growth hormone deficient patients

BackgroundPrevious studies in growth hormone (GH)-deficient (GHD) patients have indicated a possible diurnal variation in the pharmacokinetics (PK) of GH after subcutaneous (sc) GH administration. Thus, higher GH levels were observed during the night with continuous sc infusion, and increased GH bioavailability was reported following daily sc injections in the evening compared to morning. ObjectiveThe aim was to study whether diurnal variability in the PK of sc administered exogenous GH can be reproduced under standard conditions for all study participants, e.g. supine rest. Design and methodsEight male GHD patients (59.8±8years, body mass index 29.7±4.9kg/m2) received a continuous sc infusion of GH (3mg/24h) for 60h on two different occasions. Diurnal variation in PK of GH was studied during steady state in the last 24h of the infusion period. ResultsMedian GH levels were higher at night time (23:00h–07:00h) than during the day (10:00h–18:00h) for visit 1 [5.1 (4.5–7.2ng/ml/0.5h) vs. 4.6 (3.7–5.7ng/ml/0.5h); p<0.05], and reproducible results of diurnal GH variation were obtained during visit 2 [5.7 (4.6–7.4) ng/ml/0.5h vs. 4.6 (3.8–6.0) ng/ml/0.5h, p<0.05]. Reproducible results between days 1 and 2 were also obtained during 08:30h–20:30h and 20:30h–08:30h, respectively. ConclusionsPrevious findings of higher nocturnal GH levels were confirmed during steady state continuous sc GH infusion under standard conditions. The underlying mechanisms, e.g. whether GH absorption, distribution or elimination is primarily affected need to be further elucidated.

GH Mediates Exercise-Dependent Activation of SVZ Neural Precursor Cells in Aged Mice

Here we demonstrate, both in vivo and in vitro, that growth hormone (GH) mediates precursor cell activation in the subventricular zone (SVZ) of the aged (12-month-old) brain following exercise, and that GH signaling stimulates precursor activation to a similar extent to exercise. Our results reveal that both addition of GH in culture and direct intracerebroventricular infusion of GH stimulate neural precursor cells in the aged brain. In contrast, no increase in neurosphere numbers was observed in GH receptor null animals following exercise. Continuous infusion of a GH antagonist into the lateral ventricle of wild-type animals completely abolished the exercise-induced increase in neural precursor cell number. Given that the aged brain does not recover well after injury, we investigated the direct effect of exercise and GH on neural precursor cell activation following irradiation. This revealed that physical exercise as well as infusion of GH promoted repopulation of neural precursor cells in irradiated aged animals. Conversely, infusion of a GH antagonist during exercise prevented recovery of precursor cells in the SVZ following irradiation.

Acute hyperglycemia reduces myocardial blood flow reserve and the magnitude of reduction is associated with insulin resistance: a study in nondiabetic humans using contrast echocardiography

The effect of acute hyperglycemia per se on coronary perfusion in humans is undefined. We evaluated the effects of short-term hyperglycemia on myocardial blood flow reserve (MBFR) in healthy nondiabetic volunteers. Twenty-one nondiabetic volunteers (76 % females, mean ± SD, age 48 ± 5 years) had noninvasive MBFR assessment while exposed to pancreatic clamp with somatostatin and replacement glucagon and growth hormone infusions, with frequent interval plasma glucose (PG) monitoring. Insulin was infused at 0.75 mU/kg/min to mimic postprandial plasma insulin concentrations, and glucose was infused to maintain euglycemia (PG 93.9 ± 7.3 mg/dl) followed by hyperglycemia (PG 231.5 ± 18.1 mg/dl). Myocardial contrast echocardiography (MCE) was performed during each glycemic steady state using continuous infusion of Definity at rest and during regadenoson (Lexiscan 5 ml (400 μg) intravenous bolus) infusion to quantify myocardial blood flow (MBF) and determine MBFR. Insulin resistance (IR) was assessed by glucose infusion rate (GIR; mg/kg/min) at euglycemia. Median stress MBF, MBFR, and β reserve were significantly reduced during acute hyperglycemia versus euglycemia (stress MBF 3.9 vs 5.4, P = 0.02; MBFR 2.0 vs 2.7, P < 0.0001; β reserve 1.45 vs 2.4, P = 0.007). Using a median threshold GIR of 5 mg/kg/min, there was a correlation between GIR and hyperglycemic MBFR (r = 0.506, P = 0.019). MBFR, as determined noninvasively by MCE, is significantly decreased during acute hyperglycemia in nondiabetic volunteers, and the magnitude of this reduction is modulated by IR.

Increased action of pulsatile compared to non-pulsatile insulin delivery during a meal-like glucose exposure simulated by computerized infusion in healthy humans

It has previously been demonstrated that pulsatile insulin has a greater hypoglycemic effect than non-pulsatile insulin during euglycemic conditions. The aim of the present study was to examine the effect of pulsatile versus non-pulsatile insulin delivery during a meal-like iv-glucose challenge. Ten healthy young subjects were examined on two occasions. A pancreatic–pituitary clamp was maintained with somatostatin infusion and replacement of glucagon and growth hormone at baseline levels. During the first three hours on both study days, insulin was infused in a pulsatile manner. Hereafter glucose and insulin were infused by computer-controlled pumps for four hours in a pattern mimicking the postprandial glucose and insulin profiles. At one study day, insulin infusion was done in a continuous manner, while at the other study day this profile was done in a pulsatile pattern. The hypoglycemic effect of insulin was measured as the integrated area under the curve of glucose during the four-hour infusion period. The mean insulin concentration measured as the integrated area under the curve was identical (P > .9). The hypoglycemic effect of insulin was significantly augmented by 13% during pulsatile delivery as compared to continuous delivery (P = .015). Likewise was the maximal glucose concentration significantly lower at the day of the pulsatile profile (9.9 ± 1.0 vs. 11.4 ± 2.3mmol/l, P = .036). Pulsatile insulin release plays an important role in the postprandial glucose homeostasis. The disturbed insulin pulsatility in type 2 diabetes mellitus may contribute to the postprandial hyperglycemia.

Growth hormone responsive neural precursor cells reside within the adult mammalian brain

The detection of growth hormone (GH) and its receptor in germinal regions of the mammalian brain prompted our investigation of GH and its role in the regulation of endogenous neural precursor cell activity. Here we report that the addition of exogenous GH significantly increased the expansion rate in long-term neurosphere cultures derived from wild-type mice, while neurospheres derived from GH null mice exhibited a reduced expansion rate. We also detected a doubling in the frequency of large (i.e. stem cell-derived) colonies for up to 120 days following a 7-day intracerebroventricular infusion of GH suggesting the activation of endogenous stem cells. Moreover, gamma irradiation induced the ablation of normally quiescent stem cells in GH-infused mice, resulting in a decline in olfactory bulb neurogenesis. These results suggest that GH activates populations of resident stem and progenitor cells, and therefore may represent a novel therapeutic target for age-related neurodegeneration and associated cognitive decline.

Regulated recovery of pulsatile growth hormone secretion from negative feedback: a preclinical investigation

Although stimulatory (feedforward) and inhibitory (feedback) dynamics jointly control neurohormone secretion, the factors that supervise feedback restraint are poorly understood. To parse the regulation of growth hormone (GH) escape from negative feedback, 25 healthy men and women were studied eight times each during an experimental GH feedback clamp. The clamp comprised combined bolus infusion of GH or saline and continuous stimulation by saline GH-releasing hormone (GHRH), GHRP-2, or both peptides after randomly ordered supplementation with placebo (both sexes) vs. E(2) (estrogen; women) and T (testosterone; men). Endpoints were GH pulsatility and entropy (a model-free measure of feedback quenching). Gender determined recovery of pulsatile GH secretion from negative feedback in all four secretagog regimens (0.003 ≤ P ≤ 0.017 for women>men). Peptidyl secretagog controlled the mass, number, and duration of feedback-inhibited GH secretory bursts (each, P < 0.001). E(2)/T administration potentiated both pulsatile (P = 0.006) and entropic (P < 0.001) modes of GH recovery. IGF-I positively predicted the escape of GH secretory burst number and mode (P = 0.022), whereas body mass index negatively forecast GH secretory burst number and mass (P = 0.005). The composite of gender, body mass index, E(2), IGF-I, and peptidyl secretagog strongly regulates the escape of pulsatile and entropic GH secretion from autonegative feedback. The ensemble factors identified in this preclinical investigation enlarge the dynamic model of GH control in humans.

Effects of Acute Hyperglucagonemia on Hepatic and Intestinal Lipoprotein Production and Clearance in Healthy Humans

OBJECTIVEThe metabolism of hepatic- and intestinally derived lipoproteins is regulated in a complex fashion by nutrients, hormones, and neurologic and other factors. Recent studies in animal models suggest an important role for glucagon acting via the glucagon receptor in regulating hepatic triglyceride (TG) secretion. Here we examined the direct effects of glucagon on regulation of hepatic and intestinal lipoprotein metabolism in humans.RESEARCH DESIGN AND METHODSEight healthy men underwent two studies each, in random order, 4–6 weeks apart in which de novo lipogenesis, kinetics of larger VLDL1 TG, and kinetics of VLDL1 and smaller VLDL2 apolipoprotein (apo)B100 and B48 were studied using established stable isotope enrichment methods. Subjects were studied in the constant fed state under conditions of a pancreatic clamp (with infusion of somatostatin, insulin, and growth hormone) at either basal glucagon (BG study, 64.5 ± 2.1 pg/mL) or hyperglucagonemia (high glucagon [HG] study, 183.2 ± 5.1 pg/mL).RESULTSThere were no significant differences in plasma concentration of VLDL1 or VLDL2 TG, apoB100 or apoB48 between BG and HG studies. There was, however, lower (P < 0.05) VLDL1 apoB100 fractional catabolic rate (−39%) and production rate (−30%) in HG versus BG, but no difference in de novo lipogenesis or TG turnover, and glucagon had no effect on intestinal (B48-containing) lipoprotein metabolism.CONCLUSIONSGlucagon acutely regulates hepatic but not intestinal lipoprotein particle metabolism in humans both by decreasing hepatic lipoprotein particle production as well as by inhibiting particle clearance, with no net effect on particle concentration.

Peripheral administration of bovine GH regulates the expression of cerebrocortical beta-globin, GABAB receptor 1, and the Lissencephaly-1 protein (LIS-1) in adult hypophysectomized rats

Growth hormone (GH) therapy substantially improves several cognitive functions in hypopituitary experimental animals and in humans. Although a number of biochemical correlates to these effects have been characterized, there are no comprehensive analysis available examining effects of GH on the brain. Hypophysectomized female rats were given replacement therapy with cortisol and thyroxine (= hx). Subcutaneous infusions of bovine GH (bGH, henceforth designated GH) were supplied in osmotic minipumps for 6 days (= hx + GH). To evaluate whether GH normalized specific transcript expression levels in cerebral cortex, pituitary-intact rats were used as normal controls. DNA microarrays (Affymetrix) of cerebrocortical samples showed that 24 transcripts were changed by more than 1.5-fold by GH treatment in addition to being normalized by GH treatment. The expression of three selected highly regulated transcripts was confirmed by quantitative real-time polymerase chain reaction analysis. These were the GABAB receptor 1, Lissencephaly-1 protein (LIS-1), and hemoglobin b or beta-globin. A similar regulation was found for hemoglobin b also in the hippocampus. Both the GABAB receptor 1 and hemoglobin b may have importance for the previously described neuroprotective and perhaps cognitive potential of GH treatment. Altogether, these results show that short term GH treatment affects a number of transcripts in cerebral cortex with various biological functions. These transcripts represent potential novel mechanisms by which GH can interact with the brain.

Surviving Starvation: Essential Role of the Ghrelin-Growth Hormone Axis

After brief starvation, vertebrates maintain blood glucose by releasing fatty acids from adipose tissue. The fatty acids provide energy for gluconeogenesis in liver and are taken up by muscle, sparing glucose. After prolonged starvation, fat stores are depleted, yet blood glucose can be maintained at levels sufficient to preserve life. Using a new mouse model, we demonstrate that survival after prolonged starvation requires ghrelin, an octanoylated peptide hormone that stimulates growth hormone (GH) secretion. We studied wild-type mice and mice lacking ghrelin as a result of knockout of GOAT, the enzyme that attaches octanoate to ghrelin. Mice were fed 40% of their normal intake for 7 d. Fat stores in both lines of mice became depleted after 4 d. On day 7, mice were fasted for 23 h. In wild-type mice, ghrelin and GH rose massively, and blood sugar was maintained at ~60 mg/dL. In Goat(-/-) mice, ghrelin was undetectable and GH failed to rise appropriately. Blood sugar declined to ~20 mg/dL, and the animals were moribund. Infusion of ghrelin or GH prevented hypoglycemia. Our results support the following sequence: (1) Starvation lowers blood glucose; (2) glucose-sensing neurons respond by activating sympathetic neurons; (3) norepinephrine, released in the stomach, stimulates ghrelin secretion; (4) ghrelin releases GH, which maintains blood glucose. Thus, ghrelin lies at the center of a hormonal response that permits mice to survive an acute fast superimposed on chronic starvation.

Unbiased, Genome-Wide In Vivo Mapping of Transcriptional Regulatory Elements Reveals Sex Differences in Chromatin Structure Associated with Sex-Specific Liver Gene Expression

We have used a simple and efficient method to identify condition-specific transcriptional regulatory sites in vivo to help elucidate the molecular basis of sex-related differences in transcription, which are widespread in mammalian tissues and affect normal physiology, drug response, inflammation, and disease. To systematically uncover transcriptional regulators responsible for these differences, we used DNase hypersensitivity analysis coupled with high-throughput sequencing to produce condition-specific maps of regulatory sites in male and female mouse livers and in livers of male mice feminized by continuous infusion of growth hormone (GH). We identified 71,264 hypersensitive sites, with 1,284 showing robust sex-related differences. Continuous GH infusion suppressed the vast majority of male-specific sites and induced a subset of female-specific sites in male livers. We also identified broad genomic regions (up to ∼100 kb) showing sex-dependent hypersensitivity and similar patterns of GH responses. We found a strong association of sex-specific sites with sex-specific transcription; however, a majority of sex-specific sites were >100 kb from sex-specific genes. By analyzing sequence motifs within regulatory regions, we identified two known regulators of liver sexual dimorphism and several new candidates for further investigation. This approach can readily be applied to mapping condition-specific regulatory sites in mammalian tissues under a wide variety of physiological conditions.

Ghrelin O -acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice

Ghrelin O-acyltransferase (GOAT) attaches octanoate to proghrelin, which is processed to ghrelin, an octanoylated peptide hormone that stimulates release of growth hormone (GH) from pituitary cells. Elimination of the gene encoding ghrelin or its receptor produces only mild phenotypes in mice. Thus, the essential function of ghrelin is obscure. Here, we eliminate the Goat gene in mice, thereby eliminating all octanoylated ghrelin from blood. On normal or high fat diets, Goat(-/-) mice grew and maintained the same weights as wild-type (WT) littermates. When subjected to 60% calorie restriction, WT and Goat(-/-) mice both lost 30% of body weight and 75% of body fat within 4 days. In both lines, fasting blood glucose initially declined equally. After 4 days, glucose stabilized in WT mice at 58-76 mg/dL. In Goat(-/-) mice, glucose continued to decline, reaching 12-36 mg/dL on day 7. At this point, WT mice showed normal physical activity, whereas Goat(-/-) mice were moribund. GH rose progressively in calorie-restricted WT mice and less in Goat(-/-) mice. Infusion of either ghrelin or GH normalized blood glucose in Goat(-/-) mice and prevented death. Thus, an essential function of ghrelin in mice is elevation of GH levels during severe calorie restriction, thereby preserving blood glucose and preventing death.