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

Basal IGF-I levels and the GH response to at least two among provocative stimuli such as clonidine (CLO, Catapresan, 150 mcg/m2 p.o.), GHRH (1 mcg/kg i.v.)+arginine (ARG, 0.5 g/kg i.v. infusion during 30 min) and GHRH+pyridostigmine (PD, Mestinon cpr 60 mg p.o.) have been evaluated in 43 children with Prader-Willi syndrome (PWS, 17 males and 26 females, age 3-22 yr, 7 normal weight and 36 obese PWS), in 25 normal short children (NC, 17 males and 8 females, 7.7-18.5 yr) and in 24 children with simple obesity (OB, 14 males, 10 females, 7.7-21.5 yr). Both normal weight and obese PWS had mean IGF-I levels lower than those recorded in NC (p<0.001) and OB (p<0.001). The GH responses to GHRH+ARG and GHRH+PD in NC were similar and higher than that to CLO (p<0.001). In PWS the GH response to GHRH+ARG was higher than that to GHRH+PD (p<0.001) which, in turn, was higher than that to CLO (p<0.001); these responses in PWS were lower than those in normal children (p<0.02) and similar to those in OB. In normal weight PWS the GH responses to GHRH+ARG and to GHRH+PD were similar and higher than to CLO (p<0.05); however, each provocative stimulus elicited a GH rise lower than that in NC (p<0.05). In obese PWS as well as in OB the GH response to GHRH+ARG was higher than that to GHRH+PD (p<0.02) which, in turn, was higher than that to CLO (p<0.001); all GH responses in obese PWS and OB were lower than those in NC (p<0.001) but similar to those in normal weight PWS. In conclusion, patients with PWS show clear reduction of IGF-I levels as well as of the somatotroph responsiveness to provocative stimuli independently of body weight excess. These results strengthen the hypothesis that PWS syndrome is frequently connotated by GH insufficiency.
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PMID:GH/IGF-I axis in Prader-Willi syndrome: evaluation of IGF-I levels and of the somatotroph responsiveness to various provocative stimuli. Genetic Obesity Study Group of Italian Society of Pediatric Endocrinology and Diabetology. 1080 Jul 60

In this review we propose an integrated neuro-endocrine-metabolic point of view on the alterations (adaptations?) of GH/IGF-1 axis in obesity, summarizing the evidence from the literature, particularly focusing the data on humans and adding where possible results from our studies in this field. It is well-known that GH secretion is deeply impaired in overweight patients: we reviewed the multiple mechanisms underlying this issue, considering either central (CNS-related, such as impairment of GHRH tone or increased somatostatin release) or peripheral (ie metabolic: insulin, free fatty acids, glucose) factors. A central point of the debate about GH insufficiency in obesity is if it represents a simple adaptive phenomenon or reflects a true impairment of the axis activity. Evaluation of IGF-I levels and generation in obesity was the mean used to address this question: a bulk of evidence on IGF-I balance in human obesity has been provided, but the matter is still uncertain and unsolved.
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PMID:The GH/IGF-I axis in obesity: influence of neuro-endocrine and metabolic factors. 1099 20

Circulating GH levels are reduced in obesity due to true reduction of the 24-h GH production rate. GH insufficiency in obesity might reflect neuroendocrine abnormalities and/or alterations in peripheral hormones and metabolic factors. The somatotroph response to provocative stimuli including GHRH is markedly blunted in obese patients. However, the somatotroph responsiveness to GHRH in obesity shows also peculiar refractoriness to the inhibitory effect of glucose load. In this present study we aimed at verifying the effect of low dose rhIGF-I (20 microgram/kg, sc, at 0 min) on the GH response to GHRH (1 microgram/kg, iv, at 180 min) in obesity. With this goal in mind, six obese women with abdominal adiposity [OB; age (mean +/- SEM), 32.3 +/- 4.4 yr; body mass index, 32.8 +/- 2.3 kg/m(2)] were studied. The effects of recombinant human insulin-like growth factor I (rhIGF-I) administration on circulating total IGF-I, insulin, and glucose levels were also evaluated. The results in OB were compared with those recorded in age-matched lean women (NW; age, 28.3 +/- 1.2 yr; body mass index, 20.1 +/- 0.5 kg/m(2)), in whom the inhibitory effect of rhIGF-I had already been shown. Basal IGF-I levels in OB were similar to those in NW (199.7 +/- 33.3 vs. 274.4 +/- 25.3 microgram/L). The mean GH concentration over 3 h (from 0-180 min) in OB was lower than that in NW (0.9 +/- 0.4 vs. 2.6 +/- 0.8 microgram/L; P = NS). Administration of GHRH induced a GH response in OB lower than that in NW (area under the curve from 180-270 min, 576.5 +/- 137.5 vs. 1315.9 +/- 189.9 microgram/L.min; P < 0.02). Administration of rhIGF-I increased circulating IGF-I levels in both groups to the same percent extent (326.8 +/- 28.3 and 420.3 +/- 26.5 microgram/L in OB and NW, respectively). rhIGF-I administration inhibited the GH response to GHRH in OB (240.1 +/- 99.6 microgram/L; P < 0.05) as well as in NW (730.2 +/- 288.1 microgram/L; P < 0.05), although it failed to lower the mean GH concentration over 3 h in either OB or NW. After rhIGF-I the GH response to GHRH in OB was slight and was still lower (P < 0.05) than that in NW; in fact, the percent decreases were similar in both groups (44.21 +/- 14.06 and 48.21 +/- 13.95 microgram/L, in OB and NW, respectively). The mean insulin (107.1 +/- 21.9 and 36.8 +/- 7.2 pmol/L), but not glucose (4.0 +/- 0.3 and 4.1 +/- 0.1 mmol/L), levels calculated over 270 min, were higher (P = 0.005) in OB than in NW; rhIGF-I administration did not modify insulin and glucose levels in either group. Our study shows that the sc administration of a low rhIGF-I dose inhibits the somatotroph responsiveness to GHRH in obese as well as in normal subjects, indicating that somatotroph sensitivity to the inhibitory effect of rhIGF-I is preserved in obesity.
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PMID:Effects of recombinant human insulin-like growth factor I administration on the growth hormone (gh) response to GH-releasing hormone in obesity. 1123 96

The aim of this study was to evaluate the GH-releasing activity of a synthetic hexapeptide, GHRP-6, in the Prader-Willi syndrome (PWS). Sixteen PWS patients (7 males and 9 females, aged 12.7-38.3 yr), 15 with essential obesity (OB) (7 males and 8 females, aged 12.9-42.9 yr), and 8 short normal children (SN; 3 males and 5 females, aged 10.2-14.3 yr) underwent 2 tests on separate occasions, being challenged with GHRP-6 (1 microg/kg, iv) or GHRH (1 microg/kg, iv)+PD (60 or 120 mg for children or adults, po). Moreover, in 11 patients with PWS and in the group of SN, the GH response to at least 2 stimulation tests had been previously determined. GH was analyzed either as mean peak values (GHp, mcg/l), or as the area under the curve (AUC, mcg/l/h) and the net incremental area under the curve (nAUC, mcg/l/h). In the group of PWS subjects, GH responses to both GHRP-6 (GHp: 11.4+/-2.0; AUC: 588+/-113; nAUC: 483+/-108) and GHRH+PD (GHp: 7.3+/-1.8; AUC: 486+/-122; nAUC: 371+/-250) were significantly lower than those observed either in OB (GHRP-6: GHp: 25.7+/-3.2, p<0.003; AUC: 1833+/-305, p<0.005; nAUC: 1640+/-263, p<0.0001. GHRH+PD: GHp: 15.1+/-2.4, p<0.009; AUC: 1249+/-248, p<0.003; nAUC: 918+/-230, p<0.006) or in SN patients (GHRP-6: GHp: 39.1+/-3.1, p<0.0001; AUC: 2792+/-158, p<0.0001; nAUC: 2705+/-165, p<0.00005. GHRH+PD: GHp: 27.5+/-3.7, p<0.0001; AUC: 1873+/-251, p<0.0001; nAUC: 1692+/-219, p<0.0005). Unlike control groups, in PWS patients GH levels after GHRP-6 did not differ from those obtained after GHRH+PD. Interestingly, low IGF-I values were present in all PWS subjects. Furthermore, no patient with PWS showed normal GH response to the previously performed GH stimulation tests. As already reported, GH release after GHRP-6 or GHRH+PD was significantly lower in OB than in SN subjects. In conclusion, our data indicate that: 1) GH response to GHRP-6 is clearly impaired in PWS; 2) the blunted GH responses to the provocative stimuli in PWS are not an artifact of obesity; 3) short stature in PWS is caused by a complex dysfunction of the hypothalamo-pituitary structures.
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PMID:Impairment of GH responsiveness to GH-releasing hexapeptide (GHRP-6) in Prader-Willi syndrome. 1140 54

In 1994, Zhang et al. of Rockefeller University in New York reported the first successful complementary DNA (cDNA) cloning of leptin by the positional cloning method. Leptin was identified as the gene of ob/ob mouse in genetic obesity syndromes. It has very strong food intake control, and body weight and energy expenditure. The name "leptin" derived from the Greek word leptos, meaning "thin." We hereby review major advances leading to our current finding of leptin, leptin receptor and its structure, the outline of homozygote, and also influence of leptin in the pituitary. (The structure of leptin) The mouse obese gene has been localized to chromosome 6. With human leptin gene on chromosome 7q31.3, its DNA has more than 15000 base pairs and consists of three exons and two introns. For bioactivation of leptin the importance of disulfide-binding site is suggested. Human leptin which replaced the 128-th arginine with glutamine has the function of an aldosteron antagonist, which is reported to have the function of athrocytosis inhibition. The resemblance of leptin precursor of human, mouse and rat is very high, i.e., mouse and rat homology is 96% and mouse and human homology is 83%. (The structure of leptin receptor) The mutant gene, which is the cause of obesity, was shown on map on diabetic mouse (db/db) chromosome 4, and it was proven to be the same as the leptin receptor gene cloned by Tartaglia et all. Further studies have found the Zucker fatty rat (fa/fa) to be incorporated into a linkage map of rat chromosome 5, whose region of rat is the equivalent to the region of conserved synteny of the db/db mouse gene. The leptin receptor is glycoprotein consisting of a single transmembrane-spanning component. The primary structure of leptin receptor belongs to the cytokine-class1 family, the single membrane-spanning receptor, and is highly related to the gp130 signal-transducing component of the interleukin-6 (IL-6) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the leukemia inhibitory factor (LIF) receptor. The leptin receptor is known to have at least six existing isoforms (Ob-Ra, b, c, d, e, f) from the difference in splicing. (Homozygote Mutation of Leptin and Leptin Receptor :Hormone Secretion Disorders) The point mutation of ob/ob mouse and the splicing mutation of db/db mouse show remarkable obesity and hyperphagia. These obesity models show a reproduction disorder with both the male and the female, and they develop with homozygote. The cause is thought to be the gonadotropin secretory abnormality in pituitary. Three family lines report the cases of this deficiency, and it is considered that the secretory abnormality in pituitary develops into hypogonadotropic. These patients show low value in plasma FSHbeta (follicle stimulating hormone-beta and LHbeta (luteinizing hormone-beta which are produced from pituitary, and the plasma GnRH (gonadotropin releasing hormone) level is also low. Furthermore, the leptin receptor deficient family line was reported in 1998, in which case only the homozygote developed. The plasma leptin concentration of normal human is about 8.0 ng/ml, and this case with leptin receptor deficiency has high value of 500-700 ng/ml, which is the equivalent to the db/db mouse. (Role of Leptin in Hypothalamus-Pituitary-Periphery Function) The role of leptin which regulates pituitary hormones suggests the promotion the GHRH (growth hormone releasing hormone) secretion in hypothalamus-pituitary axis, with the possibility of the rise in secretion of GH (growth hormone) in pituitary, i.e. effects of icv (intracerebroventricular) infusion of leptin has spontaneously stimulated GHRH, which promotes GH secretion in the normal rats. On the other hand, topical treatment of GH3 (derived from a rat pituitary GH-secreting cell line) with leptin directly inhibits cell proliferation. The obesity model animals (ob/ob, db/db, fa/fa) have equally plump body compared to the normal models, which shows signs of sufficient growth. (Localization and Functional Relevance of Leptin and Leptin Receptor in Rodents Pituitary) Aside from being the food intake inhibitor and the energy control factor, leptin takes part in controlling the pituitary hormones. Promoting the secretion of GH, PRL (prolactin), TSHbeta (thyroid stimulating hormone-beta, FSHbeta/LHbeta, and inhibiting the secretion of ACTH (adrenocorticotropic hormone) are the major changes of pituitary hormones which are brought on by leptin. The expressive localization is specific, and immunohistochemistry (IHC) method recognized leptin in granular state in FSHbeta, LHbeta and TSHbeta positive cells. In our biochemical examination, the bulk of the expression of leptin is recognized in fraction of the secretory granule. In particular, FSHbeta cells had the highest percentage rate of colocalized leptin in rat pituitary. On the other hand, leptin receptor has been reported to be found only in normal rat pituitary, human pituitary adenoma, and respective cell lines in pituitaries by the RT-PCR method until now, but we disclosed for the first time the localization of leptin receptor on the plasma membrane of GH-secreting cells with the IHC method that has not been cleared so far. These findings show that leptin and leptin receptor have been expressed in different cells, and that the rat pituitary glands entertain paracrine mechanism between leptin (FSHbeta/LHbeta cells) and leptin receptor (GH cells). The function of paracrine in this pituitary suggests a new point of view in hypothalamus-pituitary axis, and it shall be concerned with many aspects such as hormone secretions and proliferation/inhibition. (Human Pituitary Adenoma) Preliminary report of leptin and leptin-receptor relationship with pituitary adenoma that has secretion abnormality has been filed, and its manifestation is being observed by the RT-PCR. Leptin and leptin receptor are expressed in most adenoma, and it is thought to function by autocrine and paracrine pathway in the adenomas. Leptin has been located in ACTH-secreting adenoma most frequently, especially in ACTH carcinoma. The leptin receptor is detected in all adenomas with high percentage rate, with both long and short forms, and then many cases of nonfunctioning pituitary adenomas, compared with other adenomas, have been reported to be positive with both long and short forms of leptin receptor as detected by RT-PCR. The HP75 cell line is derived from the nonfunctioning pituitary adenoma, which produces FSHbeta and LHbeta. The expression of leptin receptor in nonfunctioning pituitary adenoma, and the suppression of HP75 multiplication may lead to the possible hypothesis of leptin becoming one factor for the treatment of pituitary adenoma, especially in gonadotropin adenomas.
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PMID:Leptin and the pituitary. 1182 4

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

Obesity and starvation have opposing affects on normal physiology and are associated with adaptive changes in hormone secretion. The effects of obesity and starvation on thyroid hormone, GH, and cortisol secretion are summarized in Table 1. Although hypothyroidism is associated with some weight gain, surveys of obese individuals show that less than 10% are hypothyroid. Discrepancies have been reported in some studies, but in untreated obesity, total and free T4, total and free T3, TSH levels, and the TSH response to TRH are normal. Some reports suggest an increase in total T3 and decrease in rT3 induced by overfeeding. Treatment of obesity with hypocaloric diets causes changes in thyroid function that resemble sick euthyroid syndrome. Changes consist of a decrease in total T4 and total and free T3 with a corresponding increase in rT3. untreated obesity is also associated with low GH levels; however, levels of IGF-1 are normal. GH-binding protein levels are increased and the GH response to GHRH is decreased. These changes are reversed by drastic weight reduction. Cortisol levels are abnormal in people with abdominal obesity who exhibit an increase in urinary free cortisol but exhibit normal or decreased serum cortisol and normal ACTH levels. These changes are explained by an increase in cortisol clearance. There is also an increased response to CRH. Treatment of obesity with very low calorie diets causes a decrease in serum cortisol explained by a decrease in cortisol-binding proteins. The increase in cortisol secretion seen in patients with abdominal obesity may contribute to the metabolic syndrome (insulin resistance, glucose intolerance, dyslipidemia, and hypertension). States of chronic starvation such as seen in anorexia nervosa are also associated with changes in thyroid hormone, GH, and cortisol secretion. There is a decrease in total and free T4 and T3, and an increase in rT3 similar to findings in sick euthyroid syndrome. The TSH response to TRH is diminished and, in severe cases, thyroid-binding protein levels are decreased. In regards to GH, there is an increase in GH secretion with a decrease in IGF-1 levels. GH responses to GHRH are increased. The [table: see text] changes in cortisol secretion in patients with anorexia nervosa resemble depression. They present with increased urinary free cortisol and serum cortisol levels but without changes in ACTH levels. In contrast to the findings observed in obesity, the ACTH response to CRH is suppressed, suggesting an increased secretion of CRH. The endocrine changes observed in obesity and starvation may complicate the diagnosis of primary endocrine diseases. The increase in cortisol secretion in obesity needs to be distinguished from Cushing's syndrome, the decrease in thyroid hormone levels in anorexia nervosa needs to be distinguished from secondary hypothyroidism, and the increase in cortisol secretion observed in anorexia nervosa requires a differential diagnosis with primary depressive disorder.
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PMID:Effect of obesity and starvation on thyroid hormone, growth hormone, and cortisol secretion. 1205 88

To clarify the impairment of the GH/IGF-I axis in obstructive sleep apnea syndrome (OSAS), in 13 adult male patients with OSAS (OSA) as well as 15 weight-matched patients with simple obesity (OB) and 10 normal lean male subjects (NS), we studied: 1) the GH response to GHRH (1 micro g/kg iv) plus arginine (30 g iv); and 2) the IGF-I and IGF binding protein-3 responses to a very low dose recombinant human (rh)GH treatment (5.0 microg/kg sc per day for 4 d). The GH response to arginine plus GHRH in OSA was lower than in OB (P < 0.05), which in turn was lower than in NS (P < 0.001). Basal IGF-I levels in OSA were lower than in OB (P < 0.05), which in turn were lower than in NS (P < 0.03). As opposed to OB and NS, in OSA a very low rhGH dose did not affect IGF-I. Adjusting for age and basal values, rhGH-induced IGF-I rise in OSA was lower than in OB (P < 0.01). IGF binding protein-3, glucose, and insulin levels in the three groups were not modified by rhGH. OSA show a more marked impairment of the maximal secretory capacity of somatotroph cells together with reduced IGF-I sensitivity to rhGH stimulation. These findings suggest that OSAS is connoted by a concomitant impairment of GH secretion and sensitivity.
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PMID:Concomitant impairment of growth hormone secretion and peripheral sensitivity in obese patients with obstructive sleep apnea syndrome. 1241 71

GH secretion is regulated by hypothalamic and peripheral hormones under a very complex interplay. Superimposed on this regulation, signals of a metabolic nature connect GH secretion with the metabolic and energetic homeostasis of a given individual. GH secretion is enhanced in malnutrition and is severely impeded in obesity, but no information is available to explain why GH secretion is severely impeded or blocked in excess adiposity. Obesity is associated with high plasma levels of leptin, and leptin participates at the hypothalamic and pituitary levels in the regulation of GH secretion. Thus, it has been postulated that the inhibitory action of obesity on GH discharge may be mediated by excess leptin levels. The only situation in which obesity does not parallel leptin values is the rare case of morbid obesity due to leptin deficiency caused by missense mutation of the leptin gene. To understand the causes of GH blockade presented in obesity, patients with both homozygous and heterozygous mutations of the leptin gene and matched controls for both sex and body mass index (BMI) were studied. Three homozygous and 5 heterozygous patients with leptin gene mutations as well as 13 control subjects were studied. In all subjects basal levels of leptin and GH values stimulated by the combined administration of GHRH plus GH-releasing peptide-6 (GHRP-6) were analyzed. To analyze the effects of obesity and leptin levels, 5 groups were designed, all them matched by sex and adiposity. The number of subjects (n), leptin levels in micrograms per liter, and adiposity in BMI were as follows: nonobese subjects: n = 5, BMI = 22.1 +/- 0.9 kg/m2, leptin = 5.4 +/- 0.9; heterozygous patients: n = 5, BMI = 27.0 +/- 1.0 kg/m2, leptin = 2.3 +/- 0.1; controls for the heterozygous group: n = 5, BMI = 24.7 +/- 1.1 kg/m2, leptin = 5.7 +/- 1.2; homozygous patients: n = 3, BMI = 54.4 +/- 0.2 kg/m2, leptin = 1.0 +/- 0.2; and controls for the homozygous group: n = 3, BMI = 50.3 +/- 2.0 kg/m2, leptin = 35.0 +/- 6.6. In these matched groups, the GHRH- and GHRP-6-stimulated GH secretion (mean peak +/- SE; micrograms per liter) was: nonobese, 86.8 +/- 8.9 [significantly higher than heterozygous (28.6 +/- 4.9) and control for heterozygous (39.9 +/- 10.4)]; homozygous group, 9.4 +/- 3.0; control for homozygous, 9.3 +/- 1.0 (significantly lower than the heterozygous, control for heterozygous, and nonobese groups). Hence, it appeared that GH discharge was negatively conditioned by adiposity and was not influenced by leptin levels. To further analyze this observation, a correlation analysis showed that GH peaks were negatively correlated with BMI in the 13 control subjects as well as in the 8 leptin-deficient patients. On the contrary, the GH peaks were negatively correlated with leptin levels in controls, but showed the opposite pattern in homo- and heterozygous patients. In conclusion, the GH secretion blockade, which is characteristic of obese states, is due to adiposity or some factor linked to adiposity, but not to elevated plasma leptin levels.
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PMID:The inhibition of growth hormone secretion presented in obesity is not mediated by the high leptin levels: a study in human leptin deficiency patients. 1251 70

Ghrelin is a peptydil hormone that has recently been discovered through an unusual reverse pharmacology pathway. Ghrelin is produced mainly in the stomach, but its expression has also been demonstrated in many other organs such as pituitary, hypothalamus, bowel, kidney, heart, pancreas, testis. It is active on the central nervous system, where it is involved in the regulation of GH secretion, mainly through a GHRH-independent mechanism and directly at the pituitary level. Furthermore, ghrelin controls energy balance, enhancing fat mass deposition and food intake through the activation of the hypothalamic nuclei and the promotion of NPY (neuropeptide Y) and AGRP (Agouti related protein) expression; since it stimulates weight gain, ghrelin is considered a possible important factor in the etiology of obesity. Besides these main actions, ghrelin is active in the cardiovascular, reproductive and endocrine systems, and displays antineoplastic activity. Even though most studies have been conducted in humans and rats, there is increasing interest in the role of ghrelin in domestic species. We have integrated the first studies on ghrelin action with recent data on its involvement in modulating several central and peripheral activities.
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PMID:Ghrelin: central and peripheral effects of a novel peptydil hormone. 1296 Sep 36


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