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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review describes the recent developments in the diagnosis and treatment of states of resistance to growth hormone based mainly on the studies performed on patients with an inborn molecular defect of the growth hormone receptor, ie, Laron syndrome. Use of the polymerase chain reaction technique has facilitated the study of the defect, which in the large majority of patients resides in the extracellular domain of the growth hormone receptor. This recessively transmitted hereditary disease, characterized clinically by dwarfism and obesity and biochemically by high levels of serum human growth hormone accompanied by low serum concentrations of insulin-like growth factor I, is diagnosed mainly in inbred societies of Asian Jews, Arabs, Iranians, Italians, and Spaniards or their descendants. Isolated mutations have been found in many countries all around the world. The recent biosynthesis of insulin-like growth factor I has enabled the successful treatment of these patients, accelerating their growth, reducing their obesity, and normalizing their metabolic abnormalities resultant from the insulin-like growth factor I deficiency. The Pygmies are an inbred population in Africa, Asia, and Oceania who seemingly also have a defect in the growth hormone receptor. Acquired states of growth hormone resistance are also discussed.
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PMID:Disorders of growth hormone resistance in childhood. 837 76

Recently, two isoforms of the growth hormone-binding protein (GHBP), which is identical with the extracellular domain of the growth hormone receptor (GHR), have been described. One isoform contains the exon 3 (E3+GHBP) and one excludes the exon 3 (E3-GHBP). The distribution of both isoforms in peripheral blood and their functional relevance is so far unknown. To study the molecular distribution of both species we have analysed sera of 141 subjects with average weight, overweight and obesity by newly developed immunoassays. The relationship between the different molecular forms of GHBP and specific parameters of body composition as well as risk factors of metabolic disturbances, were then examined. The extracellular domain of the exon 3-retaining and -deleted isoforms of the GHR are released as E3+GHBP and E3-GHBP into the peripheral circulation. Furthermore, both molecular species do not show any correlation to each other (r = 0.67) and their relative proportion in blood is gender-dependent with a higher E3-GHBP proportion in females (P < 0.01). E3+GHBP appears to have a considerably stronger correlation to indicators (BMI, fat mass, waist circumference) and metabolic risk factors (fasting insulin, uric acid, triglycerides, apolipoprotein B, diastolic blood pressure) of adiposity than E3-GHBP, indicating differences in their functional significance. The availability of assays for the determination of GHBP isoforms may be very important for the study of the GH receptor and its soluble extracellular domain, GHBP.
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PMID:The exon 3-retaining and the exon 3-deleted forms of the growth hormone-binding protein (GHBP) in human serum are regulated differently. 1116 27

The present state of knowledge about growth hormone binding proteins (GHBP) is reviewed, with particular emphasis on the high affinity GHBP, which represents the circulating ectodomain of the growth hormone receptor (GHR). GHBP is conserved through vertebrate evolution, is produced in many tissues (especially liver) by either alternative GHR mRNA splicing (rodents) or by proteolytic cleavage from the GHR (humans, rabbits and several other species). The metalloprotease TACE (tumor necrosis factor-alpha converting enzyme) is the likely enzyme responsible for cleavage, but the structural requirements for TACE recognition or catalysis, and hence the precise cleavage point in the GHR, are unknown. GHBP is widely distributed in biological fluids, with marked concentration differences amongst them. GHBP binds about half of the circulating GH under basal conditions but is easily saturated at high GH levels; it subserves complex functions, including a circulating buffer/reservoir function for GH, prolongation of plasma GH half-life, competition with GHRs for GH, and probably unproductive heterodimer formation with the GHR. The net effect of these partly enhancing and partly inhibitory functions on GH action in vivo is complex and difficult to ascertain. Serum GHBP levels roughly parallel GHR expression (particularly in liver) through the life span, with very low levels in fetal life, upregulation to adult levels during childhood, and decline in senescence. Rodent pregnancy is associated with a massive increase in GHBP expression. Although the regulation of GHBP expression/production is not necessarily tightly linked to GHR expression, in general, low GHBP levels occur in conditions associated with GH resistance (e.g., malnutrition, uncontrolled diabetes, catabolic states, renal failure, hypothyroidism). Conversely, obesity, a condition with enhanced GH responsivity, is associated with elevated GHBP levels. This suggests that in many (but not all) instances of abnormal GH action, the GHBP level reflects GHR status. Laron syndrome (genetic GHR deficiency/dysfunction due to mutations in the GHR gene) is associated with low or undetectable GHBP in 75-80% of patients; GHBP measurement can therefore be used diagnostically. Depending on the design of assays for serum GH, endogenous GHBP may interfere to varying degrees, and GH assays should be individually validated and optimized in this regard. The ultimate biological role and physiological significance of the GHBP remain to be established.
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PMID:Growth hormone binding protein 2001. 1132 70

Three children of two Taiwanese families were diagnosed with Laron syndrome, two sisters and one boy. Both sets of parents were consanguineous. Clinically, all three presented with the typical craniofacies of Laron syndrome, consisting of prominent forehead and hypoplastic nasal bridge, high-pitched voice, short stature, and central obesity. Biochemically, their levels of serum IGF-I were less than 5 microg/ml before and after an IGF-I generation test, and levels of IGFBP-3 were reduced in all three patients. Sequence analysis of the growth hormone receptor gene revealed that all three carried a homozygous missense D152G mutation in exon 6.
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PMID:Clinical, biochemical and molecular investigations of three Taiwanese children with Laron syndrome. 1505 50

The growth hormone receptor (GHR) is a critical regulator of postnatal growth and metabolism. However, the GHR signaling domains and pathways that regulate these processes in vivo are not defined. We report the first knock-in mouse models with deletions of specific domains of the receptor that are required for its in vivo actions. Mice expressing truncations at residue m569 (plus Y539/545-F) and at residue m391 displayed a progressive impairment of postnatal growth with receptor truncation. Moreover, after 4 months of age, marked male obesity was observed in both mutant 569 and mutant 391 and was associated with hyperglycemia. Both mutants activated hepatic JAK2 and ERK2, whereas STAT5 phosphorylation was substantially decreased for mutant 569 and absent from mutant 391, correlating with loss of IGF-1 expression and reduction in growth. Microarray analysis of these and GHR(-/-) mice demonstrated that particular signaling domains are responsible for the regulation of different target genes and revealed novel actions of growth hormone. These mice represent the first step in delineating the domains of the GHR regulating body growth and composition and the transcripts associated with these domains.
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PMID:In vivo analysis of growth hormone receptor signaling domains and their associated transcripts. 1560 31

This study was undertaken to identify novel candidate genes at quantitative trait loci (QTL) on chicken chromosome Z (GGAZ) by comparing orthologous regions of chicken, human and mouse genomes. Primer sequences from marker flanking QTL positions (https://acedb.asg.wur.nl/) were obtained from www.iastate.edu/chickmap and blasted against the chicken genome (www.ensembl.org) using BLASTN. The best matches were those with the highest score, lowest E-values and highest percent identity. Orthologous regions in mice and humans, together with genes located on or around those loci were identified using the Ensembl website. Forty-six chicken genes, 91 mouse genes and 60 human genes associated with QTL on GGAZ were identified in the current study. Among the most promising candidate genes for egg production and egg shell quality are annexin A1 (ANXA1), osteoclast stimulating factor (OSF), thrombospondin-4 (THBS4), programmed cell death proteins (PDCD), follistatin (FST), growth hormone receptor (GHR), interferon (IFN) alpha and beta. The chicken IFN alpha and beta were located on GGAZ around position 13,000,000 bp on the draft chicken sequence map. The neuronal nicotinic acetylcholine receptor (nAChR) is located at a QTL region for abdominal fat (GGAZ 25483091 bp). Nicotine is an agonist at the nAChRs and has been shown to decrease lipolysis and triglyceride uptake, thereby reducing net storage in adipose tissue. Therefore, the nAchRs could be used as therapeutic targets for regulating feed intake and obesity. This study has identified 197 putative candidate genes in probable QTL regions of chicken chromosome Z.
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PMID:Identification of candidate genes at quantitative trait loci on chicken chromosome Z using orthologous comparison of chicken, mouse, and human genomes. 1661 Jan 37

Laron-type dwarfism is an autosomal recessive disorder caused by deletions or mutations of the growth hormone receptor gene. It is characterized by high circulating levels of growth hormone (GH) and low levels of insulin-like growth factor I (IGF-I). Patients are refractory to both endogenous and exogenous GH, and present severe growth retardation and obesity. Therapy with recombinant human insulin-like growth factor-I (rhIGF-I) accelerates linear growth. We describe a 2-year old girl with Laron syndrome, who presented with postnatal growth failure and hypoglycaemic seizures. Her evaluation disclosed high GH values during a glucagon test (peak GH value 170 ng/ml) and very low IGF I value (0.1 ng/ml) with no rise following GH administration. The growth velocity improved considerably with the administration of IGF I. Molecular analysis showed a heterozygous mutation on exon 4 of the GH receptor gene, inherited from the mother, a rather puzzling finding considering the clinical findings in mother and infant. This case constitutes the first report of Laron syndrome from Greece.
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PMID:Laron syndrome. First report from Greece. 1700 11

Growth hormone's (GH) lipolytic activity in white adipose tissue (WAT) results in decreased body fat in giant GH transgenic mice and increased subcutaneous fat in dwarf growth hormone receptor/binding protein gene-disrupted mice (GHR -/-). We therefore hypothesized that GH action would affect expression of CIDE-A (cell-death-inducing DFF45-like effector-A), a protein found in white adipose tissue (WAT) and involved in lipid metabolism. CIDE-A RNA levels were determined in subcutaneous, retroperitoneal and epididymal adipose tissue isolated from wild-type and GHR -/- mice. The adipose tissue was also analyzed for adipocyte size. We determined that the lack of GH action has depot-specific effects on the levels of CIDE-A RNA and affected adipocyte cell size. CIDE-A expression is significantly reduced in GHR -/- subcutaneous fat compared to wild-type but is not altered in retroperitoneal or epididymal fat. Likewise, adipocytes are significantly enlarged in GHR -/- subcutaneous adipose tissue relative wild-type mice. A high-fat diet also influenced the level of CIDE-A RNA in mouse adipose tissue. The high-fat diet significantly reduced CIDE-A expression in wild-type subcutaneous fat but did not alter CIDE-A expression in subcutaneous fat of GHR -/- mice. The diet also reduced CIDE-A expression in wild-type retroperitoneal fat but the levels of CIDE-A in epididymal fat were unchanged. In contrast, the high-fat diet reduced CIDE-A expression in both retroperitoneal and epididymal fat of GHR -/- mice. These data demonstrate that CIDE-A levels are reduced in two different mouse models of obesity and this reduction may contribute to altered lipid metabolism.
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PMID:CIDE-A gene expression is decreased in white adipose tissue of growth hormone receptor/binding protein gene disrupted mice and with high-fat feeding of normal mice. 1754 97

Laron syndrome is an autosomal recessive disorder caused by defects of growth hormone receptor (GHR) gene. It is characterized by severe postnatal growth retardation and characteristic facial features as well as high circulating levels of growth hormone (GH) and low levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3). This report described the clinical features and GHR gene mutations in 2 siblings with Laron syndrome in a Chinese family. Their heights and weights were in the normal range at birth, but the growth was retarded after birth. When they presented to the clinic, the heights of the boy (8 years old) and his sister (11 years old) were 80.0 cm (-8.2 SDS) and 96.6 cm (-6.8 SDS) respectively. They had typical appearance features of Laron syndrome such as short stature and obesity, with protruding forehead, saddle nose, large eyes, sparse and thin silky hair and high-pitched voice. They had higher basal serum GH levels and lower serum levels of IGF-I, IGFBP-3 and growth hormone binding protein (GHBP) than normal controls. The peak serum GH level after colonidine and insulin stimulations in the boy was over 350 ng/mL. After one-year rhGH treatment, the boy's height increased from 80.0 cm to 83.3 cm. The gene mutation analysis revealed that two patients had same homozygous mutation of S65H (TCA -->CCA) in exon 4, which is a novel gene mutation. It was concluded that a definite diagnosis of Laron syndrome can be made based on characteristic appearance features and serum levels of GH, IGF-I, IGFBP-3 and GHBP. The S65H mutation might be the cause of Laron syndrome in the two patients.
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PMID:Clinical features and growth hormone receptor gene mutations of patients with Laron syndrome from a Chinese family. 1770 34

Immune and neuroendocrine systems have bidirectional communications. Growth hormone (GH) and an orexigenic hormone ghrelin are expressed in various immune cells such as T lymphocytes, B lymphocytes, monocytes and neutrophils. These immune cells also bear receptors for hormones: growth hormone receptor (GHR) for GH and growth hormone secretagogue receptor (GHS-R) for ghrelin. The expression of GH in immune cells is stimulated by ghrelin as in anterior pituitary cells, whereas the regulation of GH secretion in the immune system by other peptides seems to be different from that in the anterior pituitary gland. Cytokines and mitogens enhance GH secretion from immune cells. GH has several biological actions in the immune system: enhancing thymopoiesis and T cell development, modulating cytokine production, enhancing B cell development and antibody production, priming neutrophils and monocytes for superoxide anion secretion, enhancing neutrophil adhesion and monocyte migration and anti-apoptotic action. Biological actions of ghrelin include attenuation of septic shock and anti-inflammatory actions, modulating phagocytosis, and enhancing thymopoiesis. The effect of ghrelin may be direct or through GH production, and that of GH may be direct or through insulin like growth factor-I (IGF-I) production. Elucidation of the roles of GH and ghrelin in the immune system may shed light on the treatment and prevention of immunological disorders such as AIDS and organ damages due to obesity/ageing-related chronic inflammation.
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PMID:Expression, regulation and biological actions of growth hormone (GH) and ghrelin in the immune system. 1914 54


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