Pulsatile Growth Hormone Secretion Research Articles

Effects of Type 1 Diabetes Mellitus on Linear Growth: A Comprehensive Review.

Type 1 diabetes mellitus (T1DM) has a significant effect on the growth of children. The disease has a negative effect on growth when considered in relation to the time period and metabolic control. Studies in this review have suggested debilitated growth in children with T1DM and have a few anomalies in the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis when compared to fit children. Some studies show that children with T1DM were taller before the onset of the disease and during early diagnosis. Moreover, the linear growth depends on the interaction between the gonadotropin hormone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroid hormones axis and GH-IGF-1; there's a rise in GH during puberty, which has an effect on the estrogen and testosterone, which leads to the pulsatile secretion of GH, this increment leads to insulin resistance. These studies suggest short stature in girls, and some suggest in both. The final height in boys was unchanged, but a slight decline was observed in girls. This review aims to provide the latest understanding of impaired heightin children with T1DM. The most accepted and effective treatment of impaired growth is the administration of long-acting insulin or continuous rapid-acting insulin. However, height was affected by the administration of good basal insulin at puberty and was unaffected by the continuous subcutaneous insulin injection. Hence, new technologies are the therapeutic regimen in children, especially the prepubertal age group; it will be interesting to see their effects on growth patterns in these children with T1DM.

Growth Hormone Secretagogues as Potential Therapeutic Agents to Restore Growth Hormone Secretion in Older Subjects to Those Observed in Young Adults.

The discovery of the growth hormone secretagogues (GHS) and the reverse pharmacology leading to the discovery of GHS receptor which enabled the identification of ghrelin as the natural ligand for the receptor have opened a new horizon in growth hormone (GH) physiology, pathophysiology, and therapeutics. Major progress has been made and we now have orally active GHS which are able to restore optimal pulsatile GH secretion which cannot be overstimulated as insulin-like growth factor feedback regulates the peaks to the optimum level. This enables GH to be restored in the older to levels normally seen in 20- to 30-year-old people; this leads to an increase in fat-free mass and redistribution of fat to the limbs. As these agents are ultimately approved and investigated further, it is likely that they will be shown to restore growth in children with moderate-to-mild GH deficiency; their benefits will be investigated in other indications such as nonalcoholic fatty liver disease, frailty, anemia, osteoporosis, and immune compromise in older subjects. The exquisite regulation of GH secretion reflects the importance of GH pulsatility in the regulation of somatotroph action of GH.

Fasting and prolonged food restriction differentially affect GH secretion independently of GH receptor signaling in AgRP neurons.

Growth hormone (GH) receptor (GHR) is abundantly expressed in neurons that co-release the agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH). Since ARHAgRP/NPY neurons regulate several hypothalamic-pituitary-endocrine axes, this neuronal population possibly modulates GH secretion via a negative feedback loop, particularly during food restriction, when ARHAgRP/NPY neurons are highly active. The present study aims to determine the importance of GHR signaling in ARHAgRP/NPY neurons on the pattern of GH secretion in fed and food-deprived male mice. Additionally, we compared the effect of two distinct situations of food deprivation: 16 h of fasting or four days of food restriction (40% of usual food intake). Overnight fasting strongly suppressed both basal and pulsatile GH secretion. Animals lacking GHR in ARHAgRP/NPY neurons (AgRP∆GHR mice) did not exhibit differences in GH secretion either in the fed or fasted state, compared to control mice. In contrast, four days of food restriction increased GH pulse frequency, basal GH secretion, and pulse irregularity/complexity (measured by sample entropy), whereas pulsatile GH secretion was not affected in both control and AgRP∆GHR mice. Hypothalamic Ghrh mRNA levels were unaffected by fasting or food restriction, but Sst expression increased in acutely fasted mice, but decreased after prolonged food restriction in both control and AgRP∆GHR mice. Our findings indicate that short-term fasting and prolonged food restriction differentially affect the pattern of GH secretion, independently of GHR signaling in ARHAgRP/NPY neurons.

OR14-4 Acute sleep disruption does not diminish pulsatile growth hormone secretion in pubertal children

Abstract Context: Growth hormone (GH) plays a critical role in glucose homeostasis and linear growth during childhood. GH secretion is controlled by multiple neurotransmitters and hormones. Sleep is also a powerful stimulus for GH secretion. In children, GH pulses occur after sleep onset in association with slow-wave sleep (SWS), but it is unclear if undisrupted sleep is required for normal GH secretion. Given the rising incidence of pediatric sleep disorders such as obstructive sleep apnea (OSA) that cause sleep fragmentation, it is critical to determine whether sleep fragmentation during childhood may dysregulate the somatotropic axis. Objective To quantify how undisrupted vs fragmented sleep affects GH secretion in children. Methods Pubertal subjects (10 M, 9 F; 9.1-14.4 yrs) were randomized to two overnight polysomnographic studies with frequent blood sampling (q10min) to measure GH: fourteen were healthy subjects studied with or without SWS disruption via auditory stimuli (3 sec, 1500 Hz tones, 40-100 dB followed by 18 sec of a 75 dB noise simulating a knock on the door) and five were subjects with OSA studied with or without prescribed continuous positive airway pressure (CPAP); the latter condition was expected to have sleep fragmentation due to untreated OSA. GH pulses were identified using sparse deconvolution. Studies without auditory stimuli or when using CPAP were combined and analyzed as 'undisrupted sleep'. The relationship between GH pulse rate per hour and sleep stage was evaluated using Poisson generalized estimating equations. Results In SWS disruption studies, an average of 77.51 ± 13.61 (range 23-190) auditory stimuli were delivered, causing a 40.02 ± 7.78% decrease in SWS in favor of lighter sleep stages. In subjects with OSA, CPAP withdrawal caused a slight increase in the apnea hypopnea index (1.08 ± 0.10 vs. 2.20 ± 1.70 events/hour of sleep, p=0.07) with no change in sleep stage durations. During undisrupted sleep, subjects had an average of 0.91 ± 0.067 GH pulses/hour with a mean pulse amplitude of 10.03 ± 1.00 ng/mL and mean basal secretion rate of 0.26 ± 0.10 ng/ml per min. GH pulses occurred more frequently during SWS (2.3 pulses/hour SWS, amplitude 9.92 ± 2.59 ng/mL) than during any other sleep stage (P < 0.001). Neither form of sleep disruption affected the distribution of GH pulses across sleep stages, GH pulse amplitude and frequency, nor basal GH secretion. Conclusion In children, nocturnal GH pulses are temporally associated with SWS. However, neither acute fragmentation of SWS nor nocturnal arousals from OSA altered basal or pulsatile GH secretion, indicating that somatotrophic axis activity is preserved in the face of acute sleep disruption in children. Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.

Acute Sleep Disruption Does Not Diminish Pulsatile Growth Hormone Secretion in Pubertal Children.

In children, growth hormone (GH) pulses occur after sleep onset in association with slow-wave sleep (SWS). There have been no studies in children to quantify the effect of disrupted sleep on GH secretion. This study aimed to investigate the effect of acute sleep disruption on GH secretion in pubertal children. Fourteen healthy individuals (aged 11.3-14.1 years) were randomly assigned to 2 overnight polysomnographic studies, 1 with and 1 without SWS disruption via auditory stimuli, with frequent blood sampling to measure GH. Auditory stimuli delivered during the disrupted sleep night caused a 40.0 ± 7.8% decrease in SWS. On SWS-disrupted sleep nights, the rate of GH pulses during N2 sleep was significantly lower than during SWS (IRR = 0.56; 95% CI, 0.32-0.97). There were no differences in GH pulse rates during the various sleep stages or wakefulness in disrupted compared with undisrupted sleep nights. SWS disruption had no effect on GH pulse amplitude and frequency or basal GH secretion. In pubertal children, GH pulses were temporally associated with episodes of SWS. Acute disruption of sleep via auditory tones during SWS did not alter GH secretion. These results indicate that SWS may not be a direct stimulus of GH secretion.

Ablation of Growth Hormone Receptor in GABAergic Neurons Leads to Increased Pulsatile Growth Hormone Secretion.

Growth hormone (GH) acts in several hypothalamic neuronal populations to modulate metabolism and the autoregulation of GH secretion via negative-feedback loops. However, few studies have investigated whether GH receptor (GHR) expression in specific neuronal populations is required for the homeostatic control of GH secretion and energy homeostasis. In the present study, we investigated the consequences of the specific GHR ablation in GABAergic (VGAT-expressing) or glutamatergic (VGLUT2-expressing) cells. GHR ablation in GABAergic neurons led to increased GH secretion, lean mass, and body growth in male and female mice. VGAT-specific GHR knockout (KO) male mice also showed increased serum insulin-like growth factor-1, hypothalamic Ghrh, and hepatic Igf1 messenger RNA levels. In contrast, normal GH secretion, but reduced lean body mass, was observed in mice carrying GHR ablation in glutamatergic neurons. GHR ablation in GABAergic cells increased weight loss and led to decreased blood glucose levels during food restriction, whereas VGLUT2-specific GHR KO mice showed blunted feeding response to 2-deoxy-D-glucose both in males and females, and increased relative food intake, oxygen consumption, and serum leptin levels in male mice. Of note, VGLUT2-cre female mice, independently of GHR ablation, exhibited a previously unreported phenotype of mild reduction in body weight without further metabolic alterations. The autoregulation of GH secretion via negative-feedback loops requires GHR expression in GABAergic cells. Furthermore, GHR ablation in GABAergic and glutamatergic neuronal populations leads to distinct metabolic alterations. These findings contribute to the understanding of the neuronal populations responsible for mediating the neuroendocrine and metabolic effects of GH.

Effects of the Isolated and Combined Ablation of Growth Hormone and IGF-1 Receptors in Somatostatin Neurons.

Hypophysiotropic somatostatin (SST) neurons in the periventricular hypothalamic area express growth hormone (GH) receptor (GHR) and are frequently considered as the key neuronal population that mediates the negative feedback loop controlling the hypothalamic-GH axis. Additionally, insulin-like growth factor-1 (IGF-1) may also act at the hypothalamic level to control pituitary GH secretion via long-loop negative feedback. However, to the best of our knowledge, no study so far has tested whether GHR or IGF-1 receptor (IGF1R) signaling specifically in SST neurons is required for the homeostatic control of GH secretion. Here we show that GHR ablation in SST neurons did not impact the negative feedback mechanisms that control pulsatile GH secretion or body growth in male and female mice. The sex difference in hepatic gene expression profile was only mildly affected by GHR ablation in SST neurons. Similarly, IGF1R ablation in SST neurons did not affect pulsatile GH secretion, body growth, or hepatic gene expression. In contrast, simultaneous ablation of both GHR and IGF1R in SST-expressing cells increased mean GH levels and pulse amplitude in male and female mice, and partially disrupted the sex differences in hepatic gene expression. Despite the increased GH secretion in double knockout mice, no alterations in body growth and serum or liver IGF-1 levels were observed. In summary, GHR and IGF1R signaling in SST neurons play a redundant role in the control of GH secretion. Furthermore, our results reveal the importance of GH/IGF-1 negative feedback mechanisms on SST neurons for the establishment of sex differences in hepatic gene expression profile.

Regulation of Sexually Dimorphic Expression of Major Urinary Proteins.

Male house mice excrete large amounts of protein in their urinary scent marks, mainly composed of Major Urinary Proteins (MUPs), and these lipocalins function as pheromones and pheromone carriers. Here, we review studies on sexually dimorphic MUP expression in house mice, including the proximate mechanisms controlling MUP gene expression and their adaptive functions. Males excrete 2 to 8 times more urinary protein than females, though there is enormous variation in gene expression across loci in both sexes. MUP expression is dynamically regulated depending upon a variety of factors. Males regulate MUP expression according to social status, whereas females do not, and males regulate expression depending upon health and condition. Male-biased MUP expression is regulated by pituitary secretion of growth hormone (GH), which binds receptors in the liver, activating the JAK2-STAT5 signaling pathway, chromatin accessibility, and MUP gene transcription. Pulsatile male GH secretion is feminized by several factors, including caloric restriction, microbiota depletion, and aging, which helps explain condition-dependent MUP expression. If MUP production has sex-specific fitness optima, then this should generate sexual antagonism over allelic expression (intra-locus sexual conflict) selectively favoring sexually dimorphic expression. MUPs influence the sexual attractiveness of male urinary odor and increased urinary protein excretion is correlated with the reproductive success of males but not females. This finding could explain the selective maintenance of sexually dimorphic MUP expression. Producing MUPs entails energetic costs, but increased excretion may reduce the net energetic costs and predation risks from male scent marking as well as prolong the release of chemical signals. MUPs may also provide physiological benefits, including regulating metabolic rate and toxin removal, which may have sex-specific effects on survival. A phylogenetic analysis on the origins of male-biased MUP gene expression in Mus musculus suggests that this sexual dimorphism evolved by increasing male MUP expression rather than reducing female expression.

Role of pulsatile growth hormone (GH) secretion in the regulation of lipolysis in fasting humans

BackgroundThe increase in growth hormone (GH) secretion during a prolonged fast stimulates lipolytic rate, thereby augmenting the mobilization of endogenous energy at a time when fuel availability is very low.Study aimTo identify the specific component of GH secretory pattern responsible for the stimulation of lipolytic rate during fasting in humans.Study protocolWe measured lipolytic rate (using stable isotope dilution technique) after an overnight fast in 15 young, healthy, non-obese subjects (11 men and 4 women), and again on four separate occasions after a 59 h fast. These four prolonged fasting trials differed only by the contents of an infusion solution provided throughout the 59 h fasting period. Subjects were infused either with normal saline (“Control”; n = 15) or with graded doses of a GH Releasing Hormone Receptor Antagonist (GHRHa):10 μg/kg/h (“High”; n = 15), 1 μg /kg/h (“Medium”; n = 8), or 0.5 μg /kg/h (“Low”; n = 6).ResultsAs expected, the 59 h fast completely suppressed plasma insulin levels and markedly increased endogenous GH concentrations (12 h vs 59 h Fast; p = 0.0044). Administration of GHRHa induced dose-dependent reduction in GH concentrations in response to the 59 h fast (p < 0.05). We found a strong correlation between the rate of lipolysis and GH mean peak amplitude (R = 0.471; p = 0.0019), and total GH pulse area under the curve (AUC) (R = 0.49; p = 0.0015), but not the GH peak frequency (R = 0.044; p = 0.8) or interpulse GH concentrations (R = 0.25; p = 0.115).ConclusionDuring prolonged fasting (i.e., 2–3 days), when insulin secretion is abolished, the pulsatile component of GH secretion becomes a key metabolic regulator of the increase in lipolytic rate.

Growth hormone receptor contributes to the activation of STAT5 in the hypothalamus of pregnant mice

Growth hormone (GH) receptor (GHR) signaling induces the phosphorylation of the signal transducer and activator of transcription 5 (pSTAT5) in the cells of several tissues including in the hypothalamus. During pregnancy, several STAT5-recruiting hormones (e.g., prolactin, GH and placental lactogens) are highly secreted. However, the precise contribution of GHR signaling to the surge of pSTAT5 immunoreactive neurons that occurs in the hypothalamus of pregnant mice is currently unknown. Thus, the objective of the present study was to determine whether GHR expression in neurons is required for inducing pSTAT5 expression in several hypothalamic nuclei during pregnancy. Initially, we demonstrated that late pregnant C57BL/6 mice (gestational day 14 to 18) exhibited increased pulsatile GH secretion compared to virgin females. Next, we confirmed that neuron-specific GHR ablation robustly reduces hypothalamic Ghr mRNA levels and prevents GH-induced pSTAT5 in the arcuate, paraventricular and ventromedial hypothalamic nuclei. Subsequently, the number of pSTAT5 immunoreactive cells was determined in the hypothalamus of late pregnant mice. Although neuron-specific GHR ablation did not affect the number of pSTAT5 immunoreactive cells in the paraventricular nucleus of the hypothalamus, reduced pSTAT5 expression was observed in the arcuate and ventromedial nuclei of pregnant neuron-specific GHR knockouts, compared to control pregnant mice. In summary, a subset of hypothalamic neurons requires GHR signaling to express pSTAT5 during pregnancy. These findings contribute to the understanding of the endocrine factors that affect the activation of transcription factors in the brain during pregnancy.

Ghrelin Gene Deletion Alters Pulsatile Growth Hormone Secretion in Adult Female Mice.

Using preproghrelin-deficient mice (Ghrl-/-), we previously observed that preproghrelin modulates pulsatile growth hormone (GH) secretion in post-pubertal male mice. However, the role of ghrelin and its derived peptides in the regulation of growth parameters or feeding in females is unknown. We measured pulsatile GH secretion, growth, metabolic parameters and feeding behavior in adult Ghrl-/- and Ghrl+/+ male and female mice. We also assessed GH release from pituitary explants and hypothalamic growth hormone-releasing hormone (GHRH) expression and immunoreactivity. Body weight and body fat mass, linear growth, spontaneous food intake and food intake following a 48-h fast, GH pituitary contents and GH release from pituitary explants ex vivo, fasting glucose and glucose tolerance were not different among adult Ghrl-/- and Ghrl+/+ male or female mice. In vivo, pulsatile GH secretion was decreased, while approximate entropy, that quantified orderliness of secretion, was increased in adult Ghrl-/- females only, defining more irregular GH pattern. The number of neurons immunoreactive for GHRH visualized in the hypothalamic arcuate nucleus was increased in adult Ghrl-/- females, as compared to Ghrl+/+ females, whereas the expression of GHRH was not different amongst groups. Thus, these results point to sex-specific effects of preproghrelin gene deletion on pulsatile GH secretion, but not feeding, growth or metabolic parameters, in adult mice.

Suppression of hyperinsulinemia restores growth hormone secretion and metabolism in obese mice.

The well-balanced secretion between insulin and growth hormone (GH) is essential in regulating substrate metabolism, energy metabolism, and body composition. High insulin and low GH levels are often observed in obesity, contributing to reduced energy expenditure and further fat accumulation. Although suppression of hyperinsulinemia is proposed as a treatment for obesity, changes in GH secretion and energy metabolism following this treatment are not thoroughly studied. This leaves unexplained observations, such as unchanged lean mass following insulin reduction. In this study, high-fat diet-induced obese (DIO) and normal chow-fed lean mice on a C57BL/6J background were treated for 7 weeks with diazoxide (1250 mg/kg in food), a KATP channel opener that suppressed insulin secretion. Diazoxide treatment for 10 days was sufficient to increase pulsatile GH secretion in DIO mice before any significant body weight change. The restored insulin-GH balance in DIO mice was followed by improvement in substrate and energy metabolism in a prolonged treatment period (4-6 weeks), including reduced fat mass, increased lipid oxidation and energy expenditure, as well as improved insulin sensitivity and metabolic flexibility. These metabolic benefits occurred along with the changes in the expression level of genes regulated by the insulin-GH balance. When applying diazoxide to normal chow-fed normoinsulinemic lean mice, none of the above metabolic effects was observed, suggesting that the metabolic changes following diazoxide treatment were mediated through the suppression of hyperinsulinemia. These results suggest that suppression of hyperinsulinemia by diazoxide restores GH secretion and improves substrate and energy metabolism in DIO mice.

Rotating Day and Night Disturb Growth Hormone Secretion Profiles, Body Energy Metabolism, and Insulin Levels in Mice

Background: Insulin and growth hormone (GH) – 2 vital metabolic regulatory hormones – regulate glucose, lipid, and energy metabolism. These 2 hormones determine substrate and energy metabolism under different living conditions. Shift of day and night affects the clock system and metabolism probably through altered insulin and GH secretion. Methods: Five-week-old male mice were randomly assigned to a rotating light (RL) group (3-day normal light/dark cycle followed by 4-day reversed light/dark cycle per week) and normal light (NL) group. Body weight and food intake were recorded every week. Series of blood samples were collected for pulsatile GH analysis, glucose tolerance test, and insulin tolerance test at 9, 10, and 11 weeks from the start of intervention, respectively. Indirect calorimetric measurement was performed, and body composition was tested at 12 weeks. Expressions of energy and substrate metabolism-related genes were evaluated in pituitary and liver tissues at the end of 12-week intervention. Results: The RL group had an increased number of GH pulsatile bursts and reduced GH mass/burst. RL also disturbed the GH secretion regularity and mode. It suppressed insulin secretion, which led to a disturbed insulin/GH balance. It was accompanied by the reduced metabolic flexibility and modified gene expression involved in energy balance and substrate metabolism. Indirect calorimeter recording revealed that RL decreased the respiratory exchange ratio (RER) and oxygen consumption at the dark phase, which resulted in an increase in fat mass and free fatty acid levels in circulation. Conclusion: RL disturbed pulsatile GH secretion and decreased insulin secretion in male mice with significant impairment in energy, substrate metabolism, and body composition.

Interleukin-2 Transiently Inhibits Pulsatile Growth Hormone Secretion in Young but not Older Healthy Men.

Interleukin-2 (IL-2), a proinflammatory cytokine, has been used to treat malignancies. Increased cortisol and adrenocorticotropin (ACTH) were noted, but growth hormone (GH) secretion was not investigated in detail. We quantified GH secretion after a single subcutaneous injection of IL-2 in 17 young and 18 older healthy men in relation to dose, age, and body composition. This was a placebo-controlled, blinded, prospectively randomized, crossover study. At 20:00 hours IL-2 (3 or 6 million units/m2) or saline was injected subcutaneously. Lights were off between 23:00 and 07:00 hours. Blood was sampled at 10-minute intervals for 24 hours. Outcome measures included convolution analysis of GH secretion. GH profiles were pulsatile under both experimental conditions and lower in older than young volunteers. Since the effect of IL-2 might be time limited, GH analyses were performed on the complete 24-hour series and the 6 hours after IL-2 administration. Total and pulsatile 24-hour GH secretion decreased nonsignificantly. Pulsatile secretion fell over the first 6 hours after IL-2 (P = .03), with visceral fat as a covariate (P = .003), but not age (P = .10). Plots of cumulative 2-hour bins of GH pulse mass showed a distinction by treatment and age groups: A temporary GH decrease of 32% and 28% occurred in the first 2-hour bins after midnight (P = .02 and .04) in young participants, whereas in older individuals no differences were present at any time point. This study demonstrates that IL-2 temporarily diminishes GH secretion in young, but not older, men.

Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease.

The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD). 92 biomarkers associated with immunity, chemotaxis, and metabolism were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized trial of tesamorelin versus placebo for 12 months. Gene set enrichment analysis was performed on serial liver biopsies targeted to immune pathways. Tesamorelin, compared to placebo, decreased interconnected proteins related to cytotoxic T-cell and monocyte activation. Circulating concentrations of 13 proteins were significantly decreased, and no proteins increased, by tesamorelin. These included 4 chemokines (CCL3, CCL4, CCL13 [MCP4], IL8 [CXCL8]), 2 cytokines (IL-10 and CSF-1), and 4 T-cell associated molecules (CD8A, CRTAM, GZMA, ADGRG1), as well as ARG1, Gal-9, and HGF. Network analysis indicated close interaction among the gene pathways responsible for these proteins, with imputational analyses suggesting down-regulation of a closely related cluster of immune pathways. Targeted transcriptomics using liver tissue confirmed a significant end-organ signal of down-regulated immune activation pathways. Long-term treatment with a GHRH analog reduced markers of T-cell and monocyte/macrophage activity, suggesting that augmentation of the GH axis may ameliorate immune activation in an HIV population with metabolic dysregulation, systemic and end organ inflammation. Clinical Trials Registration. NCT02196831.

Effect of Growth Hormone Secretagogue Receptor Deletion on Growth, Pulsatile Growth Hormone Secretion, and Meal Pattern in Male and Female Mice

Introduction: While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, in growth, feeding, and metabolism has been conducted in male rodents, very little is known about sex differences in this system. Furthermore, the role of GHS-R1a signaling in the control of pulsatile GH secretion and its link with growth or metabolic parameters has never been characterized. Methods: We assessed the sex-specific contribution of GHS-R1a signaling in the activity of the GH/IGF-1 axis, metabolic parameters, and feeding behavior in adolescent (5–6 weeks old) or adult (10–19 weeks old) GHS-R KO (Ghsr−/−) and WT (Ghsr+/+) male and female mice. Results: Adult Ghsr−/− male and female mice displayed deficits in weight and linear growth that were correlated with reduced GH pituitary contents in males only. GHS-R1a deletion was associated with reduced meal frequency and increased meal intervals, as well as reduced hypothalamic GHRH and NPY mRNA in males, not females. In adult, GH release from Ghsr−/− mice pituitary explants ex vivo was reduced independently of the sex. However, in vivo pulsatile GH secretion decreased in adult but not adolescent Ghsr−/− females, while in males, GHS-R1a deletion was associated with reduction in pulsatile GH secretion during adolescence exclusively. In males, linear growth did not correlate with pulsatile GH secretion, but rather with ApEn, a measure that reflects irregularity of the rhythmic secretion. Fat mass, plasma leptin concentrations, or ambulatory activity did not predict differences in GH secretion. Discussion/Conclusion: These results point to a sex-dependent dimorphic effect of GHS-R1a signaling to modulate pulsatile GH secretion and meal pattern in mice with different compensatory mechanisms occurring in the hypothalamus of adult males and females after GHS-R1a deletion. Altogether, we show that GHS-R1a signaling plays a more critical role in the regulation of pulsatile GH secretion during adolescence in males and adulthood in females.

Stimulation of endogenous pulsatile growth hormone secretion by activation of growth hormone secretagogue receptor reduces the fat accumulation and improves the insulin sensitivity in obese mice.

Obese individuals often show low growth hormone (GH) secretion, which leads to reduced lipid mobilization and further fat accumulation. Pharmacological approaches to increase GH levels in obese individuals by GH injection or GH-releasing hormone receptor agonist showed promising effects on fat reduction. However, side effects on glucose metabolism and the heavy costs on making large peptides hindered their clinical application. Here, we tested whether stimulation of endogenous GH secretion by a synthetic GH secretagogue receptor (GHSR) agonist, hexarelin, improved the metabolism in a hyperphagic obese mouse model. Male melanocortin 4 receptor knockout mice (MC4RKO) were pair-fed and received continuous hexarelin (10.56μg/day) or vehicle infusion by an osmotic pump for 3-4weeks. Hexarelin treatment significantly increased the pulsatile GH secretion without detectable alteration on basal GH secretion in MC4RKO mice. The treated mice showed increased lipolysis and lipid oxidation in the adipose tissue, and reduced de novo lipogenesis in the liver, leading to reduced visceral fat mass, reduced triglyceride content in liver, and unchanged circulating free fatty acid levels. Importantly, hexarelin treatment improved the whole-body insulin sensitivity but did not alter glucose tolerance, insulin levels, or insulin-like growth factor 1 (IGF-1) levels. The metabolic effects of hexarelin were likely through the direct action of GH, as indicated by the increased expression level of genes involved in GH signaling pathways in visceral adipose tissues and liver. In conclusion, hexarelin treatment stimulated the pulsatile GH secretion and reduced the fat accumulation in visceral depots and liver in obese MC4RKO mice with improved insulin sensitivity without altered levels of insulin or IGF-1. It provides evidence for managing obesity by enhancing pulsatile GH secretion through activation of GHSR in the pituitary gland.

17α-Estradiol Modulates IGF1 and Hepatic Gene Expression in a Sex-Specific Manner.

Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of the most conserved biological pathways that regulates aging across species. 17α-Estradiol (17α-E2), a diastereomer of 17β-estradiol (17β-E2), was recently found to elicit health benefits, including improved insulin sensitivity and extend longevity exclusively in male mice. Given that 17β-E2 is known to modulate somatotropic signaling in females through actions in the pituitary and liver, we hypothesized that 17α-E2 may be modulating the somatotropic axis in males, thereby contributing to health benefits. Herein, we demonstrate that 17α-E2 increases hepatic insulin-like growth factor 1 (IGF1) production in male mice without inducing any changes in pulsatile growth hormone (GH) secretion. Using growth hormone receptor knockout (GHRKO) mice, we subsequently determined that the induction of hepatic IGF1 by 17α-E2 is dependent upon GH signaling in male mice, and that 17α-E2 elicits no effects on IGF1 production in female mice. We also determined that 17α-E2 failed to feminize the hepatic transcriptional profile in normal (N) male mice, as evidenced by a clear divergence between the sexes, regardless of treatment. Conversely, significant overlap in transcriptional profiles was observed between sexes in GHRKO mice, and this was unaffected by 17α-E2 treatment. Based on these findings, we propose that 17α-E2 acts as a pleiotropic pathway modulator in male mice by uncoupling IGF1 production from insulin sensitivity. In summary, 17α-E2 treatment upregulates IGF1 production in wild-type (and N) male mice in what appears to be a GH-dependent fashion, while no effects in female IGF1 production are observed following 17α-E2 treatment.

SUN-672 SGLT2 Inhibitor Reduces Hyperinsulinemia and Restores Pulsatile Growth Hormone Secretion in Obese MC4RKO Mice

Insulin and growth hormone (GH) are crucial counter-regulatory hormones in regulating glucose and lipid metabolisms. Insulin promotes fat storage, while GH promotes lipolysis and fat oxidation. In obese individuals, reduced GH secretion (hyposomatotropism) and increased insulin secretion (hyperinsulinemia) co-exist. The imbalance of these two hormones exacerbates fat accumulation. Therapeutic approaches to correct such hormonal imbalance in obesity are limited. The sodium/glucose cotransporter 2 inhibitor (SGLT2i), which promotes urinary glucose excretion, is a novel drug for overt type 2 diabetes (T2D). However, little is known about its efficacy in obese individuals without T2D in the clinic, in particular with hormonal imbalance. By applying SGLT2i (dapagliflozin, 1 mg/kg/d for 10 weeks) to a hyperphagic obese melanocortin 4 receptor knockout (MC4RKO) mouse model, we observed a significant reduction of hyperinsulinemia (fasting: 1.36±0.19 vs. 4.93±1.04 ng/ml, p<0.01; fed: 9.50±3.37 vs. 31.11±5.85 ng/ml, p<0.05, n=8) and restored pulsatile GH secretion without changing secretion pattern (pulsatile GH: 185.3±18.37 vs. 56.28±13.22 ng/ml per 6h, p<0.001; GH mass per secretion pulse: 50.31±8.20 vs. 15.55±3.18 ng/ml, p<0.01; number of secretory pulse per 6h: 3.71±0.29 vs. 3.57±0.43, p=0.78, n=8) as early as 4 weeks after the initiation of the treatment. Lipolysis and lipid oxidation-related gene expression levels were increased by SGLT2i treatment, whereas lipogenesis and inflammation gene expression levels were reduced, leading to decreased whole-body fat mass. Following the treatment, glucose tolerance and insulin sensitivity were both improved. Although a null effect was observed in food intake and daily activity, the treatment significantly promoted lipid usage and shifted energy metabolism towards negative energy balance. In conclusion, 10-week SGLT2i treatment improved glucose and lipid metabolisms in the hyperphagic obese MC4RKO mice. Such improvement occurs alongside reduced hyperinsulinemia and restored pulsatile GH secretion. This work provides insights for the potential use of SGLT2i in obese individuals prior to overt T2D. The final version of this work is published (1).Acknowledgements: grant (NHMRC, University of Queensland) and scholarship (CSC and UQ International scholarship)Reference: (1) Huang, Zhengxiang, et al. “Dapagliflozin restores insulin and growth hormone secretion in obese mice.” Journal of Endocrinology 245.1 (2020): 1-12.Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Dapagliflozin restores insulin and growth hormone secretion in obese mice.

The well-documented hormonal disturbance in a general obese population is characterised by an increase in insulin secretion and a decrease in growth hormone (GH) secretion. Such hormonal disturbance promotes an increase in fat mass, which deteriorates obesity and accelerates the development of insulin resistance and type 2 diabetes. While the pathological consequence is alarming, the pharmaceutical approach attempting to correct such hormonal disturbance remains limited. By applying an emerging anti-diabetic drug, the sodium-glucose cotransporter 2 inhibitor, dapagliflozin (1 mg/kg/day for 10 weeks), to a hyperphagic obese mouse model, we observed a significant improvement in insulin and GH secretion as early as 4 weeks after the initiation of the treatment. Restoration of pathological disturbance of insulin and GH secretion reduced fat accumulation and preserved lean body mass in the obese animal model. Such phenotypic improvement followed with concurrent improvements in glucose and lipid metabolism, insulin sensitivity, as well as the expression of metabolic genes that were regulated by insulin and GH. In conclusion, 10 weeks of treatment with dapagliflozin effectively reduces hyperinsulinemia and restores pulsatile GH secretion in the hyperphagic obese mice with considerable improvement in lipid and glucose metabolism. Promising outcomes from this study may provide insights into drug intervention to correct hormonal disturbance in obesity to delay the diabetes progression.