A weekly administered sustained-release growth hormone reduces visceral fat and waist circumference in abdominal obesity

Administration of recombinant human growth hormone (rhGH) in obesity has been known to lead to a decrease in visceral adiposity and an increase in lean body mass. Most studies have used supraphysiological doses of rhGH, which were administered daily or every other day. We aimed to evaluate whether weekly administered low dose of sustained-release rhGH (SR-rhGH) could play a therapeutic role in the treatment of abdominal obesity. Prospective, single-arm, open-label, multicenter pilot study was carried out. Participants were 26 adults aged 40-65 years old with abdominal obesity (male: waist circumference >90?cm, female: waist circumference >85?cm). The subjects were given 3?mg of SR-rhGH, administered subcutaneously, weekly for 26 weeks. SR-rhGH treatment for 26 weeks increased the IGF-1 level by 56.53±76.09?μg/l (SDS 0.77±1.12) compared to the baseline (p=0.0022). After 26 weeks, SR-rhGH treatment reduced abdominal visceral adipose tissue (VAT) (140.35±75.97 to 128.43±73.85?cm2, p=0.0038). Average waist circumference decreased from 96.25±6.41 to 91.93±6.13?cm (p<0.0001) after treatment. However, body weight or lean body mass did not show any significant change. In conclusion, SR-rhGH treatment for 26 weeks reduced abdominal visceral fat and waist circumference without severe adverse events. Further studies may be considered on the role of weekly administered SR-rhGH as a treatment for abdominal obesity.     

Mode of growth hormone action in osteoblasts

Growth hormone (GH) affects bone size and mass in part through stimulating insulin-like growth factor type 1 (IGF-1) production in liver and bone. Whether GH acts independent of IGF-1 in bone remains unclear. To define the mode of GH action in bone, we have used a Cre/loxP system in which the type 1 IGF-1 receptor (Igf1r) has been disrupted specifically in osteoblasts in vitro and in vivo. Calvarial osteoblasts from mice homozygous for the floxed IGF-1R allele (IGF-1R(flox/flox)) were infected with adenoviral vectors expressing Cre. Disruption of IGF-1R mRNA (>90%) was accompanied by near elimination of IGF-1R protein but retention of GHR protein. GH-induced STAT5 activation was consistently greater in osteoblasts with an intact IGF-1R. Osteoblasts lacking IGF-1R retained GH-induced ERK and Akt phosphorylation and GH-stimulated IGF-1 and IGFBP-3 mRNA expression. GH-induced osteoblast proliferation was abolished by Cre-mediated disruption of the IGF-1R or co-incubation of cells with an IGF-1-neutralizing antibody. By contrast, GH inhibited apoptosis in osteoblasts lacking the IGF-1R. To examine the effects of GH on osteoblasts in vivo, mice wild type for the IGF-1R treated with GH subcutaneously for 7 days showed a doubling in the number of osteoblasts lining trabecular bone, whereas osteoblast numbers in similarly treated mice lacking the IGF-1R in osteoblasts were not significantly affected. These results indicate that although direct IGF-1R-independent actions of GH on osteoblast apoptosis can be demonstrated in vitro, IGF-1R is required for anabolic effects of GH in osteoblasts in vivo.     

Galanin: evidence for a hypothalamic site of action to release growth hormone

Galanin is a 29 amino acid peptide that was isolated and characterized from porcine intestinal extracts. The presence of galanin-like immunoreactivity in neuronal elements in the hypothalamus and median eminence suggested a role for it in the hypothalamic control of anterior pituitary function. A hypothalamic site of action of galanin to stimulate growth hormone (GH) release is suggested by our observation that doses as low as 50 picomoles when infused into the third cerebroventricle of conscious, unrestrained ovariectomized rats resulted in significantly elevated plasma levels of GH. This effect was specific for GH and was dose-related. The failure of galanin to alter GH release from dispersed, cultured anterior pituitary cells in vitro further suggests that endogenous galanin plays a neuromodulatory role at the level of the median eminence, possibly affecting the release of known GH-releasing and/or inhibiting factors.     

Ontogenesis of hepatic growth hormone receptors in the rat

Detailed ontogenic studies of the binding of human (hGH) and bovine growth hormone (bGH) have been performed in liver preparations from male and female rats during the neonatal, weanling, pre- and post-pubertal periods. Specific binding of both hormones was readily detected at all ages, with no apparent interference due to occupancy by endogenous hormones. No sex difference in binding was observed prior to weaning (22 days) for hGH, which binds to both somatotrophic and lactogenic sites. However, after weaning a marked sex-related dissociation in the pattern of binding did occur, with female rats binding 3-4 times more hGH than in the pre-weaning period and male rats binding hGH to only half their pre-weaning levels. A very similar pattern was seen for binding of bGH (which binds only to somatotrophic sites) except that in male rats, the post-weaning levels did not fall. Binding patterns for either hGH or bGH prior to weaning did not mirror the known age-related pattern of circulating rat GH levels, suggesting the absence of a definitive auto-regulation system for the GH-GH receptor system under normal circumstances in vivo. The possible role of the weaning process per se in the post-weaning changes of GH binding seen in male and female rats still requires elucidation.     

Growth hormone action in rat insulinoma cells expressing truncated growth hormone receptors

Transfection of the insulin-producing rat islet tumor cell line RIN-5AH with a full length cDNA of the rat hepatic growth hormone (GH) receptor (GH-R1-638) augments the GH-responsive insulin synthesis in these cells. Using this functional system we analyzed the effect of COOH-terminal truncation of the GH receptor. Two mutated cDNAs encoding truncated GH receptors, GH-R1-294 and GH-R1-454, respectively, were generated by site-directed mutagenesis and transfected into the RIN cells. Both receptor mutants were expressed on the cell surface and displayed normal GH binding affinity. Whereas GH-R1-638 had a molecular mass of about 110 kDa, GH-R1-294 and GH-R1-454 showed molecular masses of 49 and 80 kDa, respectively. Cells expressing GH-R1-454 internalized GH to a similar extent as cells transfected with the full length receptor and the parent cell line, but GH-R1-294-expressing cells showed a markedly reduced capability of GH internalization. In contrast to cells transfected with GH-R1-638, none of the cell lines expressing truncated GH receptors exhibited any increase of the GH-stimulated insulin production. We conclude that domains within the COOH-terminal half of the cytoplasmic part of the GH receptor are required for transduction of the signal for GH-stimulated insulin synthesis, whereas cytoplasmic domains proximal to the transmembrane region are involved in receptor-mediated GH internalization.     

Studies on tilapia hepatic growth hormone receptor.

Tilapia liver membranes were solubilized with 1% Triton X-100. The presence of growth hormone (GH) receptors was demonstrated by specific binding of radioiodinated tilapia GH (125I-tGH). The solubilized receptor possessed a molecular weight of around 400,000. It was adsorbed on Con A-Sepharose and DEAE BioGel A indicating that it contains carbohydrates and is acidic in character. Its protein nature was revealed by destruction of GH-binding activity by proteases. The involvement of essential sulfhydryl group was suggested by inhibition of 125I-tGH binding to the solubilized receptor by p-chloromercuribenzene sulfonate which could be reversed by dithioerythritol treatment.     

Regulation of the hepatic response to glucagon: role of insulin, growth hormone and cortisol

The hepatic response to glucagon was investigated in five groups of animals: (1) controls; (2) excess growth hormone (GH; tumor-bearing); (3) streptozotocin-induced diabetic; (4) cortisol-treated, and (5) insulin-treated animals. Blood samples were collected from the animal models and hepatocytes were prepared and used for glucagon-binding studies and studies of total glucose production, gluconeogenesis and glycogen determinations. Glucagon binding was elevated in GH-tumor-bearing and cortisol-treated hepatocytes but lower in hepatocytes from diabetic animals. Basal total glucose production wash higher in hepatocytes from diabetic rats but not changed in hepatocytes from GH-tumor-bearing, insulin-treated or cortisol-treated animals. Glucagon significantly stimulated total glucose production in hepatocytes from control, insulin-treated and cortisol-treated but not diabetic and GH tumor models. Gluconeogenesis as evaluated by alanine conversion to glucose was significantly increased in hepatocytes from diabetic and cortisol-treated animals and was significantly lower in hepatocytes from GH-tumor-bearing animals. Glucagon failed to significantly stimulate gluconeogenesis in hepatocytes from diabetic and tumor-bearing animals. Hepatic glycogen content was significantly decreased in diabetic and GH-tumor-bearing animals but not changed in insulin-treated and cortisol-treated animals. We conclude that increased glucagon binding was not always correlated with an increase in glucagon-stimulated glycogenolysis, gluconeogenesis or increased sensitivity to glucagon. Persistent hyperinsulinism may effectively suppress glucagon- or cortisol-stimulated pathways.     

Regulation of hepatic growth hormone receptors by insulin.

Induction of diabetes in the rat with streptozotocin caused a decrease in the specific binding of human growth hormone to liver receptors. The decrease was due to a loss of binding sites, with no change in the affinity constant for growth hormone (5.6 × 10⁹M^?1). A highly significant correlation was seen between serum insulin levels and hepatic growth hormone binding. Specific insulin binding to hepatic receptors was increased in diabetes, with a highly significant negative correlation between serum insulin levels and insulin binding. The loss of growth hormone receptors was reversed by treating diabetic rats with insulin. Since hormones which bind to “lactogenic” binding sites in the liver are reported to regulate somatomedin levels, the insulin dependence of human growth hormone receptors might account for the decrease in serum somatomedin in diabetes.     

Socioeconomic status in relation to obesity and abdominal obesity in Korean adults: a focus on sex differences

Objective: We examined the relationship between income and education level with BMI and waist circumference to provide further understanding of the relationship between socioeconomic status and obesity and to identify the presence of sex differences. Research Methods and Procedures: A total of 7962 people ≥20 years of age (3597 men; 4365 women) who participated in the 1998 Korean National Health and Nutrition Examination Survey provided data including height, weight, waist circumference, education, and income level. We examined adjusted BMI and waist circumference according to level of income and education and the association between income and education with obesity and abdominal obesity by multiple logistic regression analysis. Results: In men, significant dose‐response relationships were noted between income and obesity (trend, p < 0.05) and abdominal obesity (trend, p < 0.05). Compared with the lowest income group, the adjusted odds ratios (ORs) (95% confidence interval) of the highest income group for obesity and abdominal obesity were 1.65 (1.18 to 2.32) and 1.37 (0.94 to 1.98), respectively. However, income was not associated with obesity or abdominal obesity in the fully adjusted models in women. With regard to education, women showed significantly decreased ORs, with inverse trends for obesity and abdominal obesity across all education levels. Compared with the lowest education group, the adjusted ORs (95% confidence interval) for obesity and abdominal obesity were 0.66 (0.57 to 0.76) and 0.40 (0.35 to 0.45), respectively, among women with 7 to 12 years of schooling and 0.27 (0.21 to 0.34) and 0.15 (0.12 to 0.18), respectively, among women with 13 or more years of schooling. Discussion: Socioeconomic difference has a considerable impact on the prevalence of obesity among the Korean population, and the patterns differ substantially across sex.