Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with hypopituitarism have increased cardiovascular mortality. A high prevalence of conventional cardiovascular risk factors, including obesity, central fat distribution, insulin resistance, and dyslipidemia, have been described in these patients. The inflammatory markers C-reactive protein (CRP) and IL-6 are predictors of cardiovascular events, and high levels of CRP have been reported in men with hypopituitarism and GH deficiency. However, little is known about inflammatory cardiovascular risk markers in women with hypopituitarism. We therefore investigated whether inflammatory and traditional cardiovascular risk markers are elevated in women with hypopituitarism. Fifty-three women with hypopituitarism and 111 healthy control women were included in this cross-sectional study. Morning blood samples were drawn after an overnight fast. Serum was assayed for CRP, IL-6, glucose, insulin, IGF-I, triglycerides, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein (HDL) cholesterol, lipoprotein(a), E2, total testosterone (total T) and free testosterone (free T), and dehydroepiandrosterone sulfate. IL-6 and CRP levels were higher in women with hypopituitarism than in healthy controls (P < 0.0001 for comparison between groups). In a multivariate model, CRP levels depended on hypopituitarism, body mass index (BMI), and estrogen use. There was an interaction between the effect of BMI and hypopituitarism on CRP levels, such that the importance of hypopituitarism in determining CRP levels disappeared at high BMIs. In a similar multivariate model, IL-6 levels depended on hypopituitarism and BMI. Total cholesterol, the total to HDL cholesterol ratio, and triglycerides were higher in hypopituitary patients, but only triglycerides and the total to HDL cholesterol ratio depended on hypopituitarism when controlling for BMI. There was no significant difference in lipoprotein(a) levels between hypopituitary women and control subjects. However, when controlling for estrogen use, lipoprotein(a) levels showed a trend toward being lower in the hypopituitary group (P = 0.075). In patients with hypopituitarism, CRP correlated negatively with IGF-I (r = -0.35; P = 0.010), total T (r = -0.42; P = 0.0020), and free T (r = -0.30; P = 0.031). Similarly, IL-6 correlated negatively with total T (r = -0.39; P = 0.0040) and androstenedione (r = -0.27; P = 0.048) in hypopituitary patients. In conclusion, hypopituitary women have increased levels of IL-6 and CRP, both of which are inflammatory markers of atherosclerosis. GH deficiency and androgen deficiency may contribute to these findings. Chronic inflammation may contribute to the high cardiovascular risk seen in this population.
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PMID:Inflammatory cardiovascular risk markers in women with hypopituitarism. 1210 75

In peripheral tissues, corticosteroid hormone action is determined, in part, through the activity of 11beta-hydroxysteroid dehydrogenases (11beta-HSD), two isozymes of which interconvert hormonally active cortisol (F) and inactive cortisone (E). 11beta-HSD type 2 (11beta-HSD2) inactivates F to E in the kidney, whilst 11beta-HSD type 1 (11beta-HSD1) principally performs the reverse reaction activating F from E in the liver and adipose tissue. Alteration in expression of these 11beta-HSD isozymes in peripheral tissues modifies corticosteroid action: loss of 11beta-HSD2 activity in the kidney results in cortisol-induced mineralocorticoid excess, and loss of hepatic 11beta-HSD1 activity improves insulin sensitivity through a reduction in cortisol-induced gluconeogenesis and hepatic glucose output. Conversely, overexpression of 11beta-HSD1 in omental adipose tissue can stimulate glucocorticoid-induced adipocyte differentiation which may lead to central obesity. Patients with hypopituitarism have many clinical features in common with patients with Cushing's syndrome--notably visceral obesity, insulin resistance, osteoporosis and increased vascular mortality. Our hypothesis was that many of these features may be explained by an effect of growth hormone (GH) on the 11beta-HSD isozymes. As assessed by urinary free cortisol/urinary free cortisone ratios and endorsed through in vitro studies, neither GH nor insulin-like growth factor (IGF)-I affect 11beta-HSD2 activity. Patients with acromegaly show a reduction in hepatic-derived metabolites of cortisol/cortisone - levels return to normal when GH concentrations are normalized. Conversely, patients with GH deficiency in the setting of hypopituitarism demonstrate an increased cortisol/cortisone metabolite ratio and reduction in circulating cortisol concentrations in patients on hydrocortisone replacement. Treatment with low-dose GH replacement reverses these abnormalities. These clinical data suggest that GH (and/or IGF-I) inhibits 11beta-HSD1 (i.e. E to F conversion) (parallel in vitro studies suggest that IGF-I and not GH inhibits 11beta-HSD1). These findings have important clinical ramifications. Firstly, the GH-mediated increase in cortisol metabolism (mediated via reduced E to F conversion) may precipitate adrenal insufficiency in hypopituitary patients with partial adrenocorticotropic hormone deficiency commencing GH therapy. Secondly, many of the phenotypic features of hypopituitarism can be explained by an alteration in 11beta-HSD1 activity: GH deficiency effectively increases cortisol production in key target tissues including liver and adipose tissue, promoting insulin resistance and visceral adiposity. Thirdly, the reported beneficial effects of GH on cardiovascular risk factors in patients with hypopituitarism may be an indirect effect via alterations in cortisol metabolism. Finally, the GH/IGF-I modulation of cortisol metabolism may underpin the pathogenesis of common diseases such as central obesity and idiopathic osteoporosis. Patients with central obesity but with no evidence of hypopituitarism have relative GH deficiency and it is exciting to speculate that low-dose GH treatment in this group, by inhibiting cortisol generation within omental fat, may offer a novel therapeutic approach.
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PMID:Growth hormone, insulin-like growth factor-I and the cortisol-cortisone shuttle. 1178 77

The aim of this study was to correlate lesions of the pituitary gland with hormonal dysregulation. The hormonal status of 63 children was correlated with MRI findings of the pituitary gland. Two radiologists judged the MRI examinations without knowledge of the hormonal situation. The reliability of the diagnosis "adenoma" was evaluated in five steps from 0-100% for each sequence. A microadenoma was found in six of 14 children with hyperprolactinemia and in six of eight patients with increased IGF-I/IGFBP-3. However, microadenomas were also detected in eight of 28 children without hormonal dysfunction (clinical feature: obesity). The adenomas were seen best in a dynamic sequence after gadolinium administration. An expansive growing macroadenoma was found in one of 13 patients with hypopituitarism. We found a relatively high number of microadenomas even in children without any hormonal dysfunction. Taking into account the reported autopsy results (6.1-27% occult microadenomas), we suggest that the MRI diagnosis "microadenoma" is made too frequently if usual MRI criteria are used. Patients with increased levels of IGF-I/IGFBP-3 had a high incidence of microadenoma (up to 87.5%). Hyperprolactinemia was associated with microadenomas in about 43% (-57%) of patients (nearly on the same level as children without hormonal dysfunction). Therefore unspecific stimulation of the pituitary gland with consecutive increased volume seems to be responsible for hyperprolactinemia in many of these patients.
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PMID:Microadenomas of the pituitary gland in children with and without hypophyseal dysfunction in magnetic resonance imaging. 1187 80

Rapid infancy growth predicts childhood obesity and earlier rate of maturation. We examined whether early growth rates might also influence levels of hormones relating to growth and weight gain by measuring IGF-I, IGF-II, and leptin levels in 497 normal 5-yr-old children who were followed closely from birth. IGF-I levels at 5 yr were unrelated to cord blood IGF-I levels at birth (r = 0.03; P = 0.7; n = 166) but were positively related to current weight (r = 0.32; P < 0.0005) and height (r = 0.30; P < 0.0005) and inversely related to birthweight (r = -0.21; P < 0.0005). By body composition, IGF-I levels correlated more closely with fat-free mass (r = 0.22; P < 0.0005) than with fat mass (r = 0.12; P < 0.05), whereas leptin (r = 0.57; P < 0.0005) and IGF-II levels (r = 0.15; P < 0.005) correlated more closely with fat mass. Independent of current body composition, IGF-I levels at 5 yr were significantly associated with rate of weight gain between 0-2 yr (beta = 0.19; P < 0.0005), and children who showed postnatal catch-up growth (i.e. those who showed gains in weight or length between 0-2 yr by >0.67 SD score) had higher IGF-I levels than other children (P = 0.02). IGF-II levels at 5 yr were positively related to IGF-II levels at birth (r = 0.17; P = 0.03; n = 166), and leptin levels at 5 yr were mainly related to current adiposity. Circulating IGF-I levels in childhood are influenced by infancy growth rates and possibly mediate the effects of early postnatal nutrition on later rates of growth and maturation.
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PMID:Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate. 1188 59

Obese patients show marked impairment in spontaneous secretion as well as in the somatotroph responsiveness to all provocative stimuli. GH insufficiency in obese patients has been reported reversible after long-term diet and marked weight loss but somatotroph secretion is not restored by fasting. Among potential neuroendocrine causes, GHRH hypoactivity has been shown but it is likely that alterations in the influence of ghrelin, the gastric-derived natural ligand of the GHS-R, and or of the NPY/leptin interplay could have a role. Among metabolic alterations, the chronic elevation of FFA levels and hyperinsulinism probably have a key role in causing GH insufficiency in obesity. Despite marked GH insufficiency, total IGF-I levels are basically preserved while free IGF-I levels are even increased thus questioning real hypoactivity of GH/IGF-I axis in obesity. Peripheral GH hypersensitivity due to increased GH receptor status, hyperinsulinism and reduced IGFBP-I levels likely explain almost normal total IGF-I and increased free IGF-I levels which, in turn, probably exert an increased negative feedback action on somatotroph cells.
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PMID:Neuroendocrine and metabolic determinants of the adaptation of GH/IGF-I axis to obesity. 1199 78

Ghrelin, a natural GH secretagogue, exerts remarkable endocrine and non-endocrine activities such as orexigenic effect and modulation of the endocrine and metabolic response to variations in energy balance. Ghrelin levels have been reported to be negatively associated to insulin secretion, enhanced in anorexia and reduced in obesity. Ghrelin levels in childhood have never been evaluated. We measured morning ghrelin levels after overnight fasting in 29 healthy lean children (NC) and in 36 obese children (OBC). The results were compared with those recorded twice in 3 different sessions in healthy lean adults (NA). In NA ghrelin levels showed good within-subject reproducibility without gender-related differences. Ghrelin levels in NC [(median; 25 degrees -75 degrees centile): 426.0; 183.0-618.0 pg/ml] were similar to those in NA (380.5; 257.7-551.7 pg/ml). Ghrelin levels in OBC (229.5; 162.5-339.5 pg/ml) were lower (p<0.03) than in NC (426.0; 183.0-618.0 pg/ml). Both in NC and in OBC, ghrelin levels were independent of gender and pubertal status. In all children, ghrelin levels were negatively associated (p<0.05) to weight excess (r=-0.24), insulin (r=-0.28) and IGF-I (r=-0.4) levels. In conclusion, these findings demonstrate that morning ghrelin levels after overnight fasting show good within-subject reproducibility, and are similar in both sexes and do not vary from childhood to adulthood. In childhood, circulating ghrelin levels are reduced in obese subjects being negatively correlated to overweight and insulin secretion.
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PMID:Circulating ghrelin levels as function of gender, pubertal status and adiposity in childhood. 1203 50

This study was designed to explore whether low doses of recombinant human (rh)GH affect lipid, glucose, or protein metabolism in men with visceral obesity. Four different studies were performed in six, otherwise healthy, obese men (age, 42 +/- 3; body mass index, 33 +/- 1 kg/m(2); waist circumference, 111 +/- 3 cm; mean +/- SEM). Lipid, glucose, and protein kinetics was estimated by infusing stable isotopes (glycerol, glucose, leucine) in the basal state and after 1 wk of treatment with sc bedtime injections of either placebo, 2.5 (GH2.5), or 3.3 (GH3.3) microg rhGH/kg body weight per day. When compared with baseline, placebo had no effect on lipid, glucose, or protein fluxes. In contrast, GH2.5 and GH3.3 increased lipolysis by approximately 25% (P < 0.04) without changing glucose and protein turnover rates. The two rhGH treatments increased within the normal range serum IGF-I (by approximately 30%; P < 0.01), whereas they augmented insulin secretion (P < 0.04) in a dose-dependent manner (GH2.5 by 19%, GH3.3 by 37%). C-peptide secretion was increased (P = 0.01) only by GH3.3 (by 28%). In conclusion, 1 wk of treatment with low doses of rhGH is sufficient to increase lipolysis in visceral obese men, but it does not modify glucose and protein turnover rates. The results of this study provide the rationale to design clinical trials using low doses of rhGH to attempt to reduce fat mass.
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PMID:Short-term treatment with low doses of recombinant human GH stimulates lipolysis in visceral obese men. 1210 8

Expanded adipose tissue mass increases the risk for many clinical conditions including diabetes, hypertension, coronary atherosclerotic heart disease, and some forms of cancer. Therefore, it is imperative that we understand the mechanisms by which fat pads expand. The enlargement of fat cells during the development of obesity has been previously hypothesized to be a triggering factor for the proliferation of new fat cells. There is now a preponderance of evidence that adipose tissue is a source of growth factors such as IGF-I, IGF binding proteins, TNF alpha, angiotensin II, and MCSF that are capable of stimulating proliferation. The relative importance of these autocrine/paracrine factors in the normal control of preadipocyte proliferation is unknown. In addition, the proliferative response of preadipocytes to the paracrine milieu is undoubtedly modulated by neural inputs to fat tissue and/or serum factors. Together, these multiple regulatory controls orchestrate overall and region-specific adipose tissue cellularity responses associated with the development of hyperplastic obesity. Both in vivo and in vitro studies are needed to understand the complex, interacting physiological mechanisms by which growth of this important organ is regulated.
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PMID:The biology of white adipocyte proliferation. 1211 95

Previous investigations of adults with the Prader-Willi syndrome (PWS) are few and have demonstrated severe obesity with increased morbidity and mortality in cardiovascular disease. It is, thus, important to identify risk factors and, if possible, start prevention. We studied the clinical, genetic, endocrinological, and metabolic findings in 19 adult PWS patients (10 men; mean age, 25 yr). The PWS karyotype was demonstrated in 13 patients. The mean body mass index was 35.6 kg/m(2), and total body fat was increased. Two thirds were biochemically hypogonadal. Fifty percent had severe GH deficiency (GHD). Four were hypertensive. One patient had heart failure and diabetes. Impaired glucose tolerance was seen in 4 patients, elevated homeostasis model assessment index in 9 patients, and modest dyslipidemia in 7. IGF-binding protein-1 correlated negatively with insulin levels. Four patients had osteoporosis, and 11 had osteopenia. There was no significant difference between the group with the PWS karyotype and the group without the karyotype in age, body mass index, waist/hip ratio, percent body fat, insulin values, homeostasis model assessment index, or lipid profile, except for lipoprotein(a), which was significantly higher in the group with the negative karyotype. IGF-I and lumbar spine bone mineral density were significantly lower in patients with genetic alteration, indicating a more severe GHD. The risk factors found in this study predicting cardiovascular disease are interpreted as secondary to GHD. These findings point to the importance of evaluating treatment of GHD in adults with PWS.
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PMID:Metabolic profile and body composition in adults with Prader-Willi syndrome and severe obesity. 1216 80

Obesity is associated with considerably reduced plasma GH concentrations, which may contribute to anovulation in (obese) women with polycystic ovary disease (PCOS). This clinical investigation was undertaken to establish whether the GH release process is deranged in obese women with PCOS and, if so, whether the observed anomalies are features of the syndrome or a sequel of body fat accretion. To this end we sampled 24-h plasma GH concentration profiles at 10-min intervals in 15 obese PCOS patients [mean age, 29 yr (range, 20-38); percent body fat, 47 +/- 5.2%], 15 equally obese controls with regular menstrual cycles [age, 34 yr (range, 20-44); percent body fat, 48 +/- 4.9%], and 15 healthy age-matched lean controls [age, 34 yr (range, 21-45); percent body fat, 29 +/- 9.0%]. Compared with lean controls, obese PCOS patients exhibited a greater than 60% reduction in basal and a greater than 75% reduction in pulsatile and total daily GH secretion due to a 2.7-fold attenuation of burst mass and a lesser (1.4-fold) slowing of GH pulse frequency. The mean +/- SEM number of statistically significant GH peaks was 13.9 +/- 1.2/24 h, the endogenous GH half-life was 14.1 +/- 0.4 min, basal GH secretion was 5.0 +/- 0.7 mU/liter.24 h, and total secretion was 61.4 +/- 9.6 mU/liter.24 h in obese women with PCOS. None of these parameters differed from those in the body mass index-matched controls. The approximate entropy ratio was significantly increased in obese women (both PCOS and controls), indicating greater irregularity of the GH release process. Total GH secretion in patients and the two control groups correlated strongly and negatively with percent body fat (r = -0.775; P < 10(-8)). Serum concentrations of IGF-I and IGF-binding protein-3 were higher in patients with PCOS than in obese controls (P = 0.03 and P = 0.02, respectively), but the IGF-1/IGF-binding protein-3 ratio was equivalent in all three study groups. In conclusion, the profoundly reduced and irregular GH release in obese women with PCOS appears to be a corollary of body fat accretion and not of the syndrome per se.
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PMID:Low amplitude and disorderly spontaneous growth hormone release in obese women with or without polycystic ovary syndrome. 1221 75


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