leptin and Dwarfism--Pituitary

The US Food and Drug Administration approved use of recombinant human growth hormone (GH) for the treatment of idiopathic short stature (ISS) in children; however, few studies have evaluated metabolic outcomes. This article addresses whether children with ISS treated with GH experience the same metabolic benefits as children with GH deficiency (GHD) treated with GH. A systematic review of all published studies of GH treatment in children with ISS that included data on metabolic outcomes identified five studies. No meta-analysis has been performed.Studies show a metabolic response to GH treatment in children with ISS similar to that observed in children with GHD; effects include a transient decrease in insulin sensitivity and a dose-dependent increase in insulin-like growth factor I. However, no increase in the risk of diabetes was found. Children with ISS seem to benefit from GH treatment in terms of height gain without any severe negative metabolic outcomes.

Topics: Adipose Tissue; Adolescent; Body Height; Child; Dwarfism; Dwarfism, Pituitary; Glucose; Growth Disorders; Human Growth Hormone; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Lipid Metabolism; Male; Recombinant Proteins

Topics: Adipose Tissue; Adult; Animals; Dwarfism, Pituitary; Fatty Acids, Nonesterified; Human Growth Hormone; Humans; Leptin

Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses.. Short prepubertal children with either isolated GHD (39) or ISS (89) participated in a 2-year randomized trial of either individualized GH treatment with six different GH doses (range, 17-100 microg/kg/day) or a standard dose (43 microg/kg/day).. To evaluate if individualized GH treatment reduced the variance of the metabolic measures as shown for growth response and to compare changes in metabolic variables in children with ISS and GHD.. Individualized GH dose reduces the range of metabolic outcomes, and metabolic outcomes are similar in children with ISS and GHD.. We observed a narrower variation for fasting insulin (-34.2%) and for homoeostasis model assessment (HOMA) (-38.9%) after 2 years of individualized GH treatment in comparison with standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (Delta) height SDS correlated with Deltainsulin-like growth factor I (IGF-I), Deltaleptin and Deltabody composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [Deltalean body mass (LBM) SDS and DeltaIGF-I SDS] clustered together and correlated strongly with Deltaheight SDS and GH dose, whereas lipolytic variables [Deltafat mass (FM) SDS and Deltaleptin] were clustered separately from anabolic variables. Regression analysis showed GH dose dependency in ISS, and to a lesser degree in GHD, for DeltaLBM SDS and Deltaheight SDS, but not for changes in FM.. Individualized GH dosing during catch-up growth reduces the variance in insulin and HOMA and results in equal metabolic responses irrespective of the diagnosis of GHD or ISS.

Topics: Adiponectin; Analysis of Variance; Body Composition; Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Dwarfism, Pituitary; Female; Growth Disorders; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Principal Component Analysis; Prospective Studies; Time Factors; Treatment Outcome

Mice in which the genes for growth hormone (GH) or GH receptor (GHR(-/-) ) are disrupted from conception are dwarfs, possess low levels of IGF-1 and insulin, have low rates of cancer and diabetes, and are extremely long-lived. Median longevity is also increased in mice with deletion of hypothalamic GH-releasing hormone (GHRH), which leads to isolated GH deficiency. The remarkable extension of longevity in hypopituitary Ames dwarf mice can be reversed by a 6-week course of GH injections started at the age of 2 weeks. Here, we demonstrate that mutations that interfere with GH production or response, in the Snell dwarf, Ames dwarf, or GHR(-/-) mice lead to reduced formation of both orexigenic agouti-related peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) projections to the main hypothalamic projection areas: the arcuate nucleus (ARH), paraventricular nucleus (PVH), and dorsomedial nucleus (DMH). These mutations also reduce hypothalamic inflammation in 18-month-old mice. GH injections, between 2 and 8 weeks of age, reversed both effects in Ames dwarf mice. Disruption of GHR specifically in liver (LiGHRKO), a mutation that reduces circulating IGF-1 but does not lead to lifespan extension, had no effect on hypothalamic projections or inflammation, suggesting an effect of GH, rather than peripheral IGF-1, on hypothalamic development. Hypothalamic leptin signaling, as monitored by induction of pStat3, is not impaired by GHR deficiency. Together, these results suggest that early-life disruption of GH signaling produces long-term hypothalamic changes that may contribute to the longevity of GH-deficient and GH-resistant mice.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Carrier Proteins; Dwarfism, Pituitary; Growth Hormone; Inflammation; Insulin; Insulin-Like Growth Factor I; Leptin; Liver; Longevity; Male; Mediodorsal Thalamic Nucleus; Mice; Mice, Inbred C57BL; Mice, Knockout; Paraventricular Hypothalamic Nucleus; Pro-Opiomelanocortin; STAT3 Transcription Factor

We aimed to determine the significance and changes in leptin, adiponectin (ADP), and visfatin levels in adults with growth hormone deficiency (GHD). Forty adults (19 men, 21 women) who had been diagnosed with GHD comprised the observation group, while 36 healthy adults (18 men, 18 women) were used as the control group. Fasting venous blood was collected to detect leptin, ADP, and visfatin levels. There was no statistically significant difference (P > 0.05) between the GHD group and the control group in terms of gender ratio, age, and body mass index. The waist-to-hip ratio (0.894 ± 0.061 vs 0.830 ± 0.481), cholesterol (4.99 ± 1.046 vs 4.18 ± 0.683), triglyceride (1.97 ± 1.428 vs 1.08 ± 0.403), LDL (2.91 ± 0.980 vs 2.29 ± 0.540), leptin (3.00 ± 1.233 vs 1.89 ± 1.554), ADP (15.26 ± 6.449 vs 10.24 ± 7.608), and visfatin levels (10.42 ± 3.715 vs 5.87 ± 3.90) in the GHD group were significantly higher than those in the control group (all P < 0.05). The levels of growth hormone (1.68 ± 1.67 vs 15.53 ± 6.23), insulin-like growth factor-1 (IGF-1, 22.64 ± 16.41 vs 61.85 ± 28.48), IGF-binding protein-3 (4889 ± 2962 vs 6866 ± 3823), and dehydroepiandrosterone sulfate (1.466 ± 1.804 vs 6.000 ± 2.767) in the GHD group were significantly lower than those in the control group (all P < 0.05). Correlation analysis demonstrated that leptin level was positively correlated to ADP and visfatin in both the GHD and control groups and negatively correlated to IGF-1 (r = 0.332, P < 0.05). Logistic regression analysis demonstrated that leptin, ADP, and visfatin were independent risk factors for adults with GHD.

Topics: Adiponectin; Adult; Body Composition; Body Mass Index; Cholesterol; Cytokines; Dwarfism, Pituitary; Female; Human Growth Hormone; Humans; Leptin; Male; Nicotinamide Phosphoribosyltransferase; Risk Factors; Triglycerides; Waist-Hip Ratio

Growth hormone deficiency (GHD) leads to growth failure and changes in body composition including increased fat accumulation and reduced lean body mass in both humans and rodents. The aim of this study was to characterize the consequences of isolated GHD (IGHD) on adiposity, total body weight (TBW), and food intake in a mouse model of autosomal recessive IGHD due to targeted ablation of the GH-releasing hormone (GHRH) gene [GHRH knockout (GHRHKO)]. Animals were also analyzed with respect to leptin, adiponectin and visfatin circulating levels and gene expression in both intra-abdominal and subcutaneous fat.. We studied 8 male mice homozygous for GHRHKO allele (-/-) and 8 heterozygous (+/-) animals as controls. Feeding and TBW data were collected weekly from 3 through 5 months of age. Animals were then euthanized for measurement of body length and intra-abdominal (epididymal and retroperitoneal) and subcutaneous (interscapular, axillary, gluteal and inguinal) fat weights, and for blood collection for leptin, adiponectin and visfatin measurement. Gene expression of leptin, adiponectin and visfatin in adipose tissue was evaluated by real-time reverse transcription polymerase chain reaction.. GHRHKO mice had significantly increased relative intra-abdominal (P<0.01) and subcutaneous (P<0.0001) fat, accompanied by significantly increased food intake per TBW (P<0.01), whereas - despite 40% higher food consumption--TBW change was not different from controls over the 2 month period. Adiponectin and visfatin mRNA levels were decreased in both intra-abdominal (P<0.001) and subcutaneous fat (P<0.0001), while leptin mRNA levels were not different from controls. Conversely, serum adiponectin levels were higher in GHRHKO mice (P<0.0001), whereas serum visfatin and leptin did not significantly differ from controls.. IGHD due to targeted ablation of the GHRH gene in mice is associated with increased relative subcutaneous and intra-abdominal fat mass and higher food consumption which is not related to changes in circulating leptin.

Topics: Adipokines; Adipose Tissue; Animals; Dwarfism, Pituitary; Eating; Growth Hormone-Releasing Hormone; Heterozygote; Homozygote; Leptin; Male; Mice; Mice, Knockout; Nicotinamide Phosphoribosyltransferase; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

This study describes the previously uncharacterized ontogeny and regulation of truncal adipose reserves in the profoundly GH-deficient dwarf (dw/dw) rat. We show that, despite normal proportionate food intake, dw/dw rats develop abdominal leanness and hypoleptinemia (circulating leptin halved in dw/dw males, P < 0.05) during puberty. This contrasts with the hyperleptinemia seen in moderately GH-deficient Tgr rats (circulating leptin doubled at 6 wk of age, P < 0.05) and in GH receptor-binding protein (GHR/BP)-null mice (circulating leptin doubled; P < 0.05). This lean/hypoleptinemic phenotype was not completely normalized by GH treatment, but dw/dw rats developed abdominal obesity in response to neonatal MSG treatment or maintenance on a high-fat diet. Unlike Tgr rats, dw/dw rats did not become obese with age; plasma leptin levels and fat pad weights became similar to those in wild-type rats. In contrast with truncal leanness, tibial marrow adiposity was normal in male and doubled in female dwarves (P < 0.01), this increase being attributable to increased adipocyte number (P < 0.01). Neonatal MSG treatment and high-fat feeding elevated marrow adiposity in dw/dw rats by inducing adipocyte enlargement (P < 0.05). These results demonstrate that, despite lipolytic influence of GH, severe GH deficiency in dw/dw rats is accompanied by a paradoxical leanness. This lean/hypoleptinemic phenotype is not solely attributable to reduced GH signaling and does not appear to result from a reduction in nutrient intake or the ability of dw/dw adipocytes to accumulate lipid. Disruption of preadipocyte differentiation or adipocyte proliferation in the dw/dw rat may lead to the development of this unusually lean/hypoleptinemic phenotype.

Topics: Abdominal Fat; Animals; Animals, Genetically Modified; Body Weight; Cohort Studies; Dwarfism, Pituitary; Eating; Female; Food Additives; Insulin-Like Growth Factor I; Leptin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Rats; Sodium Glutamate; Tibia