Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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

Insulin, insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), and obesity, and in particular visceral obesity, are putative cancer risk factors. Little is known, however, about the relationship between IGFs and obesity. We investigated the relationship between adipose tissue distribution and IGF-1 and IGFBP-3. Single-slice abdominal computed tomography scanning through the L4-L5 interspace was used to measure visceral adipose tissue (VAT) and subcutaneous adipose tissue (SQAT) in 432 community-based subjects (267 men, 165 women; ages, 55-77), participating in a cancer screening trial. Insulin, IGF-1, IGFBP-3, and the ratio of IGF-1:IGFBP-3, measured by radioimmunoassay, were compared with age, body mass index, absolute and relative VAT and SQAT, and total abdominal fat. We found that men had a higher mean IGF-1 (129.5 versus 108.9 ng/ml; P < 0.0001) and more VAT (201.5 cm(3) versus 166.6 cm(3); P < 0.0001) than women. In men and women, there was no correlation between IGF-1, IGFBP-3, or the ratio of IGF-1:IGFBP-3 with body mass index, total fat, VAT or SQAT, or fasting insulin. In contrast, fasting insulin was highly correlated to all measures of obesity (P = 0.0001). We conclude that obesity, adipose tissue distribution, and in particular VAT are not correlated with IGF-1, IGFBP-3, or the molar ratio of IGF-1:IGFBP-3. The lack of association between obesity and the IGF-1 axis suggests that the IGF-1 axis is not a likely mediator between VAT and disease.
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PMID:Lack of association between adipose tissue distribution and IGF-1 and IGFBP-3 in men and women. 1281 10

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

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

A functioning growth hormone (GH)-insulin-like growth factor (IGF)-I axis is ordinarily essential for normal growth. In several physiological and pathophysiological conditions, however, growth without GH has been described. GH-deficient newborns can have a length within the normal range, which suggests that other growth factors dominate longitudinal gain during gestation. Obese children grow at a normal rate despite their low serum GH levels and reduced response to pharmacological stimulation tests. Children with hypopituitarism secondary to craniopharyngioma resection may continue to grow and may even show growth rate acceleration if their weight increases significantly. Several possible mechanisms might underlie the growth stimulation in obese children, such as elevated levels of insulin and reduced levels of IGF binding protein-1. Recently, elevated leptin levels in obese children were found to affect the bone growth center, and it may be that leptin also participates in the growth without GH observed in obesity, especially after craniopharyngioma removal. Sex hormones stimulate growth in children with a normal GH-IGF-I axis. In the absence of GH, the sex hormones stimulate growth through a direct GH-independent effect on the bone growth centers. Leptin, insulin, and sex hormones locally activate the IGF system in the epiphyseal growth plate (EGP). Other, undiscovered hormones and growth factors may harbor the ability to directly influence the growth processes in the EGP.
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PMID:Growth without growth hormone. 1251 Sep 77

Inflammatory processes, marked in part by the acute phase reactant C-reactive protein (CRP) and insulin resistance are implicated in atherogenesis. Low insulin-like growth factor-I (IGF-I) and IGF binding protein-1 (IGFBP-1) concentrations are closely associated with insulin resistance. We examined CRP in ethnic groups with differing risk for cardiovascular disease and type 2 diabetes and its relationship with insulin sensitivity (Homeostasis model assessment (HOMA)-S) and the IGF system. European (n=155), Pakistani (n=108) and African-Caribbean (African Caribbean) (n=177) origin participants were randomly sampled from population registers. All underwent basic anthropometry, glucose tolerance testing and measurement of insulin sensitivity, CRP and other metabolic variables. CRP was significantly lower in African Caribbean men and women than in other ethnic groups. Across all groups CRP correlated negatively with (HOMA-S) (rho=-0.29, P<0.001). Regression analysis which included ethnicity and body mass index (BMI) showed that low HOMA-S (beta=-0.17, P<0.001) and low IGFBP-1 (beta=-0.14, P<0.001) were independently and inversely associated with CRP, but the effect was modified by obesity. In obese subjects insulin sensitivity was not associated with CRP. However, for the whole population, a 2.7 mg/l increase in CRP was associated with a 50% (95% confidence interval (CI) 10-210%) greater risk of WHO defined metabolic syndrome, independent of IGF-I (odds ratio (OR) 0.46 (95% CI 0.22-0.96)), IGFBP-1 (OR 0.58 (0.44-0.76)), female sex (OR 0.43 (0.22-0.84)), NEFA (OR 1.06 (1.03-1.09)) and Pakistani ethnicity. High CRP (as a measure of chronic subclinical inflammation), low IGF-I and low IGFBP-1 are independently associated with the presence of the metabolic syndrome and with insulin resistance. In obese subjects insulin sensitivity is not associated with changes in CRP whilst in non-obese subjects CRP independently contributes to variation in HOMA-S.
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PMID:C-reactive protein and the insulin-like growth factor (IGF)-system in relation to risk of cardiovascular disease in different ethnic groups. 1295 85

Circulating IGF binding protein (IGFBP)-1 levels have been associated with insulin sensitivity, the metabolic syndrome, several cardiovascular risk factors, and possibly with cancer. We examined long-term nutrient intake and metabolic and anthropometric factors in relation to IGFBP-1 levels in 226 men, 42-76 yr old, who completed 14 24-h diet recall interviews. Spearman rank correlation coefficients were calculated. Serum IGFBP-1 levels were significantly inversely correlated with insulin, homeostasis model assessment-insulin resistance, and IGF-I and positively correlated with age. Furthermore, IGFBP-1 was inversely correlated with anthropometric measures reflecting obesity, somewhat stronger in middle-aged (<65 yr) than in older men. Serum IGFBP-1 increased with higher energy and carbohydrate intake but only in the younger age group. The difference in mean IGFBP-1 levels comparing men in the top quartile of carbohydrate intake with those in the bottom quartile was 45% in men of age 42-54 yr (P = 0.01). Insulin, body mass index, and carbohydrate intake together explained 39% of the variability in IGFBP-1 levels in men 42-54 yr of age, 27% in men 55-64 yr, and 6% in men 65 or more years old. Our data suggest that metabolic, anthropometric, and nutritional factors are important determinants of IGFBP-1 levels in healthy men.
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PMID:Metabolic, anthropometric, and nutritional factors as predictors of circulating insulin-like growth factor binding protein-1 levels in middle-aged and elderly men. 1507 Sep 59

Simple childhood obesity is characterized by normal or even accelerated growth in spite of reduced growth hormone (GH) secretion. There are conflicting reports on the effects of obesity upon components of the GH-insulin-like growth factor-I (IGF-I)-IGF binding proteins (IGFBPs) system. In the present study we aimed to determine GH, IGF-I, IGFBP-3 and IGFBP-2 as well as some of the less explored components of this axis (IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments, and total acid labile subunit [ALS]) in 22 obese and 17 age-matched control children. We also evaluated not only total GH binding protein (GHBP) serum levels but also GHBP bound to GH (complexed) in both groups. Obese and control groups strongly differed in BMI (obese: 4.7 +/- 0.36 vs control: 0.37 +/- 0.25 SDS, p <0.0001). In the obese group, we found lower GH serum levels, but normal serum levels of GH-GHBP complex, IGF-I, IGFBP-3, IGF-I/IGFBP-3 molar ratio, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Obese children presented higher total circulating GHBP (6.0 +/- 0.44 vs 2.9 +/- 0.29 nmol/l, p <0.001) and insulin levels (10.5 +/- 1.5 vs 5.1 +/- 0.8 mU/l, p <0.001), while IGFBP-2 (4.6 +/- 0.5 vs 6.6 +/- 0.7%, p <0.05) and the ratio IGFBP-2/IGF-I (0.032 +/- 0.019 vs 0.095 +/- 0.01, p = 0.013) were lower than in controls. BMI and insulin were directly, and IGFBP-2 serum levels inversely, correlated to total GHBP serum levels when multiple regression analysis was performed (r = 0.74, p <0.001). By stepwise regression analysis, insulin (r = -0.37, p <0.05) and BMI (r = -0.52, p <0.01) inversely determined IGFBP-2. In summary, obese children present normal growth in spite of reduced GH secretion, probably because the combination of increased total GHBP and normal GH-GHBP complex serum levels (suggesting increased GH receptor [GHR] number and a normal serum GH reservoir, respectively) allow for the achievement of normal levels of IGF-I, IGFBP-3, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Reduced IGFBP-2 serum levels and a lower ratio of IGFBP-2/IGF-I in obese children may suggest an increase of tissue IGF-I bioavailability, thus promoting its action. Normal IGF-I and GH availability may be contributing to maintain normal growth in obese children.
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PMID:Differential impact of simple childhood obesity on the components of the growth hormone-insulin-like growth factor (IGF)-IGF binding proteins axis. 1523 10

To delineate the roles of the lactogens and GH in the control of perinatal and postnatal growth, fat deposition, insulin production, and insulin action, we generated a novel mouse model that combines resistance to all lactogenic hormones with a severe deficiency of pituitary GH. The model was created by breeding PRL receptor (PRLR)-deficient (knockout) males with GH-deficient (little) females. In contrast to mice with isolated GH or PRLR deficiencies, double-mutant (lactogen-resistant and GH-deficient) mice on d 7 of life had growth failure and hypoglycemia. These findings suggest that lactogens and GH act in concert to facilitate weight gain and glucose homeostasis during the perinatal period. Plasma insulin and IGF-I and IGF-II concentrations were decreased in both GH-deficient and double-mutant neonates but were normal in PRLR-deficient mice. Body weights of the double mutants were reduced markedly during the first 3-4 months of age, and adults had striking reductions in femur length, plasma IGF-I and IGF binding protein-3 concentrations, and femoral bone mineral density. By age 6-12 months, however, the double-mutant mice developed obesity, hyperleptinemia, fasting hyperglycemia, relative hypoinsulinemia, insulin resistance, and glucose intolerance; males were affected to a greater degree than females. The combination of perinatal growth failure and late-onset obesity and insulin resistance suggests that the lactogen-resistant/GH-deficient mouse may serve as a model for the development of the metabolic syndrome.
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PMID:Roles of the lactogens and somatogens in perinatal and postnatal metabolism and growth: studies of a novel mouse model combining lactogen resistance and growth hormone deficiency. 1538 48

Hyperinsulinemia, hyperglycemia, and elevated insulin-like growth factor (IGF)-1 levels have been implicated in the etiology of colorectal cancer. However, the joint effects of insulin and IGF-I have not been considered, and whether hyperinsulinemia or hyperglycemia is more etiologically relevant is unclear. IGF binding protein-1 (IGFBP-1) has been hypothesized to mediate the effects of insulin, but epidemiologic data on IGFBP-1 are sparse. We conducted a nested case-control study among the 32,826 women of the Nurses' Health Study who provided a blood sample in 1989 to 1990. After excluding diabetics, we confirmed 182 incident colorectal cancer cases over 10 years of follow-up and 350 controls. Cases were matched to two controls on year of birth, date of blood draw, and fasting status. C-peptide levels were weakly associated with risk of colon cancer [top quartile (Q4) versus bottom quartile (Q1): multivariable relative risk (MVRR), 1.76; 95% confidence interval (95% CI), 0.85-3.63]. Fasting IGFBP-1 was inversely associated with risk of colon cancer (MVRR, 0.28; 95% CI, 0.11-0.75). We observed no clear association between glycosylated hemoglobin and risk for colorectal cancer. The IGF-I to IGFBP-3 molar ratio was associated with colon cancer risk (MVRR, 2.82; 95% CI, 1.35-5.88), and women with low levels of both IGF-I/IGFBP-3 and C-peptide (or high IGFBP-1) were at low risk, and elevation of either was sufficient to increase risk. Although altering IGF-I levels may not be practical, the growing burden of obesity and consequently hyperinsulinemia, which seems increasingly important for colon cancer, may be a target for effective prevention.
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PMID:A prospective study of C-peptide, insulin-like growth factor-I, insulin-like growth factor binding protein-1, and the risk of colorectal cancer in women. 1582 55


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