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)

It has occasionally been suggested that GH directly suppresses circulating IGFBP-1 levels, although it is generally believed that such an effect is secondary to a GH-induced increase in insulin levels. We present data from several experiments in which the effects of GH on IGFBP-1 could be studied more extensively. In normal subjects (n = 36), an i.v. GH bolus caused a small but significant decrease in plasma IGFBP-1 concentrations without changes in insulin [IGFBP-1 (microgram/l): 2.6 +/- 0.3 (GH) vs 3.2 +/- 0.4 (placebo), P < 0.05]. Conversely, a 28-h somatostatin infusion with and without GH administration during fasting in normal subjects yielded higher IGFBP-1 levels in the non-GH substituted study [50.5 +/- 5.3 (GH-suppression) vs 22.6 +/- 5.6 (GH-substitution), P < 0.01], comparable with an increased concentration of IGFBP-1 during fasting in GH-deficient patients without usual GH substitution [23.4 +/- 7.6 (GH pause) vs 14.1 +/- 4.9 (GH substitution), P < 0.01]. In both fasting studies insulin levels remained stable. During a hypocaloric diet, long-term GH treatment in obesity lead to a significant decline in IGFBP-1 level (2.3 +/- 0.6 vs 1.2 +/- 0.2, P < 0.01), while no changes were found in the placebo group. Again, insulin levels remained equally low in both studies. Finally, a significant rebound increase in IGFBP-1 level in response to insulin induced hypoglycemia was only observed among GH-deficient patients, but not in control subjects, the latter of whom responded to hypoglycemia with a significant increase in serum GH levels [23.2 +/- 7.2 (GHDA) vs 2.5 +/- 0.3 (controls), P < 0.01]. In conclusion, a suppressive effect of GH on IGFBP-1 appears to be unmasked in the presence of low or suppressed insulin levels, making GH a potential regulator of IGF-1 bioactivity in a hitherto unrecognized way.
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PMID:Evidence supporting a direct suppressive effect of growth hormone on serum IGFBP-1 levels. Experimental studies in normal, obese and GH-deficient adults. 1020 8

The mouse ob gene encodes leptin, an adipocyte hormone that regulates body weight and energy expenditure. Leptin has potent metabolic effects on fat and glucose metabolism. A mutation of the ob gene results in mice with severe hereditary obesity and diabetes that can be corrected by treatment with the hormone. In lean mice, leptin acutely increases glucose metabolism in an insulin-independent manner, which could account, at least in part, for some of the antidiabetic effect of the hormone. To investigate further the acute effect of leptin on glucose metabolism in insulin-resistant obese diabetic mice, leptin (40 ng x g(-1) x h(-1)) was administered intravenously for 6 h in C57Bl/6J ob/ob mice. Leptin increased glucose turnover and stimulated glucose uptake in brown adipose tissue (BAT), brain, and heart with no increase in heart rate. A slight increase in all splanchnic tissues was also noticed. Conversely, no increase in skeletal muscle or white adipose tissue (WAT) glucose uptake was observed. Plasma insulin concentration increased moderately but neither glucose, glucagon, thyroid hormones, growth hormone, nor IGF-1 levels were different from phosphate-buffered saline-infused C57Bl/6J ob/ob mice. In addition, leptin stimulated hepatic glucose production, which was associated with increased glucose-6-phosphatase activity. Conversely, PEPCK activity was rather diminished. Interestingly, hepatic insulin receptor substrate (IRS)1-associated phosphatidylinositol 3-kinase activity was slightly elevated, but neither the content of glucose transporter GLUT2 nor the phosphorylation state of the insulin receptor and IRS-1 were changed by acute leptin treatment. Hepatic lipid metabolism was not stimulated during the acute leptin infusion, since the content of triglycerides, glycerol, and citrate was unchanged. These findings suggest that in ob/ob mice, the antidiabetic antiobesity effect of leptin could be the result of a profound alteration of glucose metabolism in liver, BAT, heart, and consequently, glucose turnover. Insulin resistance of skeletal muscle and WAT, while not affected by acute leptin treatment, could also be corrected in the long term and account for some of leptin's antidiabetic effects.
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PMID:Acute intravenous leptin infusion increases glucose turnover but not skeletal muscle glucose uptake in ob/ob mice. 1034 14

Caloric restriction (CR), from approximately 3 months of age, at 70% of the ad libitum (AL) caloric intake prevented development of overt obesity in female "viable yellow" Avy/A (BALB/cStCrlfC3Hf/Nctr x VY/WffC3Hf/Nctr-Avy) F1 hybrid mice. In adult yellow Avy/A mice, caloric restriction eliminated the increased metabolic efficiency associated with the presence of agouti protein in ectopic sites. At 4 weeks of age, the yellow Avy/A mice were approximately 14% heavier and by 12 weeks of age, when caloric restriction began, they were approximately 24% heavier than the congenic agouti A/a mice. Between 4 and 12 weeks, the yellow mice gained approximately 63% in body weight, whereas the agouti mice gained only approximately 44%. While the comparable AL Avy/A mice gained approximately 128% and the AL A/a mice gained approximately 41% between 12 and 51 weeks of age, the CR Avy/A and A/a mice gained only 16% and 15%, respectively. Mean brain weights of CR mice of both genotypes were lower than those of the comparable ad libitum-fed (AL) groups; however, CR Avy/A mice had slightly, but significantly (P < 0.0001), higher brain weights than CR A/a mice. The larger mean brain weight and retention, during caloric restriction, of the somewhat greater prerestriction Avy/A mean body weight compared with prerestriction A/a mice were consonant with the hypothesis that ectopic agouti protein affects somatic growth directly or indirectly. This may be related to altered developmental/metabolic programming in yellow mice, indicated by greater metabolic efficiency and by an early transient increase in circulating IGF-1 levels. The specific cellular processes modulated by the agouti protein in ectopic sites remain to be identified.
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PMID:Caloric restriction abolishes enhanced metabolic efficiency induced by ectopic agouti protein in yellow mice. 1035 19

Patients with myelomeningocele show an increased incidence of endocrinological disorders during their childhood. These disorders can ulteriorly affect the adult height of these patients who are already extremely short. In the present study we determined the final height in 21 patients (11 females aged 20.55 +/- 3.54 years; 10 males aged 20.99 +/- 2.94 years) with myelomeningocele. The endocrinological implications were investigated by clinical and laboratory assessment at control and an accurate retrospective evaluation of individual clinical history. Auxological data indicated that in male patients mean final height was significantly less (P < 0.05) than target height, but in females the difference between final height and target height was even more marked (P < 0.001). Comparison of SDS for adult height between males (-2.04 +/- 1.89) and females (-4.36 +/- 2.24) evidenced a statistically significant difference (P < 0.05). The analysis of endocrinological data showed that 7 females had had precocious puberty not treated; no case of precocious puberty was evidenced in males. In 4 females we observed plasmatic IGF-1 and IGFBP-3 concentrations significantly reduced either for chronological age and pubertal stage; this finding emerged in only 1 male. Plasmatic thyroid hormone and adrenal steroid concentrations resulted normal in both groups. Finally, obesity, considered as BMI > 90%, resulted present since childhood in 4 females and 2 males. Our data show that females with myelomeningocele have a statistically greater decrease of their adult stature respect to males. This difference is probably due to a more significant incidence in females of endocrinological diseases. Thus, we believe that a better statural prognosis may be joined in these patients (particularly in girls), through a careful endocrinological follow-up, performed from their births, in order to ensure a prompt identification and treatment of the cases of precocious puberty, impaired GH secretion or obesity.
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PMID:[Precocious puberty, Gh deficiency and obesity can affect final height in patients with myelomeningocele: comparison of males and females]. 1057 Jul 85

A variety of external factors interacting with genetic susceptibility influence the carcinogenesis process. External factors including oxidative compounds, electrophilic agents, and chronic infections may enhance genetic damage. In addition, various hormonal factors which influence growth and differentiation are critically important in the carcinogenic process. Diet and nutrition can influence these processes directly in the gastrointestinal tract by providing bioactive compounds to specific tissues via the circulatory system, or by modulating hormone levels. Differences in certain dietary patterns among populations explain a substantial proportion of cancers of the colon, prostate and breast. These malignancies are largely influenced by a combination of factors related to diet and nutrition. Their causes are multifactorial and complex, but a major influence is the widespread availability of energy-dense, highly processed and refined foods that are also deplete in fiber. These dietary patterns in combination with physical inactivity contribute to obesity and metabolic consequences such as increased levels of IGF-1, insulin, estrogen, and possibly testosterone. These hormones tend to promote cellular growth. For prostate cancer, epidemiologic studies consistently show a positive association with high consumption of milk, dairy products, and meats. These dietary factors tend to decrease 1.25(OH)2 vitamin D, a cell differentiator, and low levels of this hormone may enhance prostate carcinogenesis. While the nutritional modulation of growth-enhancing and differentiating hormones is likely to contribute to the high prevalence of breast, colorectal, prostate, and several other cancers in the Western world, these cancers are relatively rare in less economically developed countries, where malignancies of the upper gastrointestinal tract are quite common. The major causes of upper gastrointestinal tract cancers are likely related to various food practices or preservation methods other than refrigeration, which increase mucosal exposure to irritants or carcinogens.
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PMID:Nutritional factors in human cancers. 1073 13

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

Both central obesity and osteoporosis are common findings in states of glucocorticoid excess. In many tissues, including adipose tissue, hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyses the inter-conversion of active glucocorticoid, cortisol (F) and inactive cortisone (E) and regulates exposure to the glucocorticoid receptor. As such, factors which regulate 11beta-HSD1 are likely to have an important role in adipose tissue and bone physiology. Using primary cultures of human adipose stromal cells we have investigated the effect of various factors present within the adipocyte microenvironment for their effects on 11beta-HSD1 expression. IGF-1 caused a dose dependant inhibition of 11beta-HSD1 activity in both subcutaneous and omental stromal cells. Additionally, TNFalpha treatment increased 11beta-HSD1 reductase activity and mRNA expression. In adult human bone, 11beta-HSD1, but not 11beta-HSD2, expression was demonstrated using enzyme activity studies, RT-PCR and immunohistochemistry. In contrast to liver and adipose tissues, where reductase activity predominates, both reductase and dehydrogenase activities of 11beta-HSD1 were evident in bone chips and primary cultures of human osteoblasts. The action of growth factors and cytokines on glucocorticoid sensitive tissues such as adipose tissue and bone may be mediated by modulation of local glucocorticoid metabolism at a pre-receptor level.
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PMID:The role of 11 beta-hydroxysteroid dehydrogenase in central obesity and osteoporosis. 1119 47

Neuropeptide Y (NPY) in the hypothalamus exerts multiple physiological functions including stimulation of adipogenic pathways such as feeding and insulin secretion as well as inhibition of the somatotropic and gonadotropic axes. Since hypothalamic NPY-ergic activity is increased by negative energy balance, NPY enables coordinated regulation of growth and reproduction in parallel with energy availability. Chronic pathological increases in central NPY-ergic activity contribute to obesity. Many of the adipogenic effects of NPY are specifically dependent on adrenal glucocorticoids. However, in the current study we show that central NPY does not require adrenal hormones to inhibit the somatotropic and gonadotropic axes in rats. Male adrenalectomized and sham-operated normal rats were intracerebroventricularly (ICV) infused with NPY (15 microg/day) or saline for 5-7 days, and plasma leptin, insulin-like growth factor (IGF-1) and testosterone were assayed, and epididymal white adipose tissue (WATe) was weighed. In normal intact rats, WATe weight and leptinemia were significantly increased by NPY, and these effects were prevented by adrenalectomy. In normal rats, NPY markedly reduced plasma IGF-1 levels (470 +/- 40 versus 1260 +/- 90 ng/ml) and testosterone (0.53 +/- 0.28 versus 5.4 +/- 0.80 nmol/l in saline-infused controls, p < 0.0001). Adrenalectomy decreased plasma IGF-1 concentrations to 290 +/- 30 (p < 0.0001 versus normal rats), which were significantly reduced further by NPY. However, adrenalectomy had no significant effect on basal nor on NPY-induced plasma testosterone concentrations. In conclusion unlike the stimulatory effects of NPY on fat mass and leptinemia, NPY-induced inhibition of the somatotropic and gonadotropic axes in male rats do not require adrenal hormones.
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PMID:Inhibitory effects of central neuropeptide Y on the somatotropic and gonadotropic axes in male rats are independent of adrenal hormones. 1128 3

Kidney dysfunction and mesangial enlargement are consequences of obesity found in Zucker rats. This study examines some of the early mechanisms by which the kidneys of Zucker rats undergo these changes. Our study shows that the glomerular planar area in the genetically obese Zucker rat undergo enlargement as early as 12 weeks of life, compared to the lean controls. This suggests mesangial proliferation is already occurring at this time, earlier than previously shown. The mRNA expression for IGF-I, and GHR in the kidney and liver of the obese Zucker rats were significantly reduced compared to the lean controls. However, the mRNA of the IGF-IR was significantly elevated in the kidney of the obese Zucker rats. The increase in kidney IGF-1R mRNA in the obese Zucker rat may suggest an increase in IGF-1 binding leading to the kidney hypertrophy observed in these rats.
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PMID:mRNA expression for insulin-like growth factor 1, receptors of growth hormone and IGF-1 and transforming growth factor-beta in the kidney and liver of Zucker rats. 1144 85

The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiology research of recent years. There is increasing evidence that alterations in the fetal environment may have long-term consequences on cardiovascular, metabolic, and endocrine pathophysiology in adult life. This process has been termed programming, and we have shown that undernutrition of the mother during gestation leads to programming of hyperphagia, obesity, hypertension, hyperinsulinemia, and hyperleptinemia in the offspring. Using this model of maternal undernutrition throughout pregnancy combined with postnatal hypercaloric nutrition of the offspring, we examined the effects of IGF-I therapy. Virgin Wistar rats (age 75 +/- 5 d, n = 20 per group) were time mated and randomly assigned to receive food either ad libitum or 30% of ad libitum intake (UN) throughout pregnancy. At weaning, female offspring were assigned to one of two diets (control or hypercaloric [30% fat]). Systolic blood pressure was measured at day 175 and following infusion with 3 microg/g per day recombinant human IGF-1 (rh-IGF-I) by minipump for 14 d. Before treatment, UN offspring were hyperinsulinemic, hyperleptinemic, hyperphagic, obese, and hypertensive on both diets, compared with ad libitum offspring and this was exacerbated by hypercaloric nutrition. IGF-I treatment increased body weight in all treated animals. However, systolic blood pressure, food intake, retroperitoneal and gonadal fat pad weights, and plasma leptin and insulin concentrations were markedly reduced with IGF-I treatment. IGF-I treatment resulted in a 3- to 5-fold increase in 38--44 kDa and 28--30 kDa IGF binding proteins, although in UN animals, there was an impaired and differential up-regulation of these insulin-like growth factor binding proteins following IGF-I treatment. The 24-kDa IGF binding protein representing IGF binding protein-4 was down-regulated in all IGF-I-treated animals, but the decrease was more marked in UN animals. Our data suggest that IGF-I treatment alleviates hyperphagia, obesity, hyperinsulinemia, hyperleptinemia, and hypertension in rats programmed to develop the metabolic syndrome X.
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PMID:IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming. 1151 75


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