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)

Obesity in childhood is characterized by subnormal integrated concentrations of growth hormone (IC-GH) and elevated integrated concentrations of insulin (IC-I). We tested whether a reduction of IC-I induced by a low calorie diet would lead to a rise of IC-GH into the normal range for age. Six obese children (body mass index (BMI) 39.1 +/- 9.2 kg/m2) underwent integrated concentration (IC) studies by continuous withdrawal before and again 5-8 weeks after being on a low calorie diet. In response to the diet BMI was lower 34.7 +/- 9.4 kg/m2 (P less than 0.003), and IC-I was considerably reduced, 479 +/- 255 pM initially vs. 109 +/- 109 pM on the diet, P less than 0.0008. IC-GH increased modestly from 1.6 +/- 0.6 micrograms/l initially to 2.4 +/- 0.6 micrograms/l, P less than 0.01 on the diet. None of the patients had repeat IC-GH levels which were above the lower limit of normal for lean children of normal stature (3.2 micrograms/l). Single sample insulin-like growth factor 1 (IGF-1) levels were unchanged: 40.9 +/- 23.1 nM initially vs. 49.7 +/- 25.7 nM (314.6 +/- 197.7 vs. 382.5 +/- 217.0 ng/ml, n.s.). Thus reduction of high insulin concentrations during 5-8 weeks of a low calorie diet has only a small effect on IC-GH in obese children. Factors other than circulating insulin levels are likely to play the major role in mediating the reduced levels of GH observed in obesity.
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PMID:Reduction of plasma insulin levels does not restore integrated concentration of growth hormone to normal in obese children. 132 72

Adipsin is a serine protease with complement factor D activity that is synthesized by adipocytes and secreted into the blood stream. Expression of adipsin is deficient in models of genetic (ob/ob, db/db) and acquired (monosodium glutamate-lesioned) obesity, but the cellular mechanisms responsible for this deficiency are unknown. Because hyperinsulinemia is frequently associated with obesity, we evaluated the effects of this hormone and insulin-like growth factor 1 (IGF-1) on adipsin secretion and adipsin messenger RNA (mRNA) levels in 3T3-F442A adipocytes. In the present study, we report that in fully differentiated adipocytes (after 11 days post confluence), insulin exposure progressively decreases adipsin secretion by 40%, 67%, and 78% after 2, 4, and 6 days of treatment. The inhibition of adipsin secretion by insulin is the result of a corresponding decrease in adipsin mRNA and is specific since two other differentiation-dependent fat cell mRNAs encoding aP2 (a fatty acid binding protein) and glycerophosphate dehydrogenase (GPD), are unaffected. Insulin suppresses adipsin gene expression via high affinity insulin receptors, because physiological levels of insulin produce this effect, and dose-response curves for insulin stimulation of 2-deoxyglucose uptake and glucose utilization are similar to insulin's effect on adipsin. In contrast, insulin when present during days 1-8 post confluence (during differentiation) markedly increases adipsin secretion and adipsin mRNA levels. This stimulation is due to the ability of insulin to accelerate differentiation as evidenced by corresponding increases in aP2 and GPD mRNAs as well. Insulin and IGF-1 are equipotent in this effect, suggesting that both insulin and IGF-1 receptors can mediate this response. In summary, during the differentiation of 3T3-F442A adipocytes, insulin stimulates adipsin gene expression by accelerating differentiation. As the cells become mature adipocytes, they acquire some differentiation-dependent factor, which couples insulin receptor stimulation to inhibition of adipsin gene expression. This model should aid our search for the molecular links between insulin receptor stimulation and altered gene expression.
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PMID:Differentiation dependent biphasic regulation of adipsin gene expression by insulin and insulin-like growth factor-1 in 3T3-F442A adipocytes. 224 32

Metabolic disorders including diabetes mellitus, glucose intolerance, dyslipidemias, hyperuricemia, and hypervitaminosis A have often been mentioned in association with diffuse idiopathic skeletal hyperostosis (DISH). Production of bone under the influence of insulin or retinol has been suggested as a possible mechanism for this disease. We prospectively studied metabolic disorders in 25 patients with DISH and 25 controls matched for age, sex, and body mass index. Correlations between simultaneously evaluated parameters were looked for. Obesity was prevalent in both groups. Serum levels of glucose, insulin, glycated hemoglobin, total cholesterol, HDL cholesterol, triglycerides, uric acid, retinol, and retinol binding protein were similar in the two groups. A positive correlation was found between body mass index and serum insulin. We found no correlation between serum levels of insulin and retinol. None of the metabolic parameters studied showed alterations likely to explain the development of hyperostosis. Other growth factors such as retinoic acid or insulin-like growth factor 1, perhaps produced on a paracrine basis, may be the cause of increased bone at enthesis production.
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PMID:[Forestier disease and metabolism disorders. A prospective controlled study of 25 cases]. 816 24

Earlier onset of menarche and tallness in adult women are mainly confirmed as risk markers for breast cancer. Recent disparate case-control studies have reported abdominal-type obesity and higher circulating levels of insulin, testosterone and insulin-like growth factor 1, to be further risk markers for breast cancer. There is evidence that abdominal-type obesity is recognisable in girls even before puberty, and disparate studies have shown it to be correlated with earlier onset of menarche, insulin resistance leading to hyperinsulinaemia, and an abnormal sex steroid profile. The implications are that earlier onset of puberty in a subset of girls can lead to more prolonged exposure of developing breast tissue to an abnormal sex steroid profile and also to a higher circulating level of insulin. It is postulated that these metabolic/endocrine concomitants of abdominal-type obesity could play a role in promoting mammary carcinogenesis at a young age, particularly if genetic predisposition is present.
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PMID:Does early physical maturity influence breast cancer risk? 820 71

Massive obesity is always accompanied by insulin resistance with hyperinsulinaemia in proportion to the amount of visceral fat, which has repercussions on oxidative and non-oxidative glucose metabolism. The increase of free fatty acids in direct relation to the adipocytic mass reduces the hepatic insulin uptake; it increases the suprahepatic glucose flow and the production of very low density lipoproteins. The adipose tissue exerts a feminizing effect in men and a masculinizing effect in women. Women have disorders of ovulation and hirsutism, with increase of free testosterone and elevation of luteotropic hormone levels. Men have hypoandrism due to excessive aromatization of androgens and oestrogens. The adipose tissue accelerates the turnover of cortisol and facilitates cortisone production, which stimulates ACTH secretion and maintains stimulation of the adrenal cortex. Hyperinsulinism and resistance to insulin also intervene in hormonal regulation. They elevate the insulin-like growth factor 1 (IGF-1) which inhibits the production of growth hormone and reduces its plasma half-life; hyperinsulinism and IGF-1 facilitate ovarian androgen production; hypothalamic disturbances occur by diminution of sensitivity to hypoglycaemia, and there are abnormalities in monoaminergic and serotoninergic control. Bone tissue density is preserved for a long time, as it is in proportion to the fatty mass and to the oestrogen and IGF-1 levels, but it may be gradually reduced by secondary hyperparathyroidism. Thyroid function and thyrotropic regulations are unaffected.
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PMID:[Endocrine and metabolic consequences of massive obesity]. 831 Feb 48

We recently reported the frequent occurrence of polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy, especially when the medication was started before the age of 20 years. In the present study we evaluated the association of obesity and hyperinsulinemia with valproate-related polycystic ovaries and hyperandrogenism in women with epilepsy. Sixty-five women participated in the study. Twenty-two received valproate monotherapy and 43 received carbamazepine monotherapy. In addition to clinical examination, vaginal ultrasonography was performed to determine ovarian size, and the concentrations of serum sex hormones, insulin, insulin-like growth factor 1, and the insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1 and IGFBP-3) were measured. Fifty-nine percent of the women on valproate were obese, and in a retrospective analysis an indisputable weight gain (mean, 21 kg; range, 8-49 kg) was found in 50% of the women taking valproate. Fourteen (64%) of the women on valproate had polycystic ovaries, hyperandrogenism, or both. These women were obese, and in addition to elevated serum androgen levels, they had high concentrations of fasting serum insulin and low levels of serum insulin-like growth factor-binding protein 1. Valproate therapy for epilepsy is associated with weight gain during treatment in approximately 50% of women patients. The weight gain can be progressive, and is associated with hyperinsulinemia and low serum levels of insulin-like growth factor-binding protein 1, which may lead to hyperandrogenism and polycystic ovaries.
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PMID:Obesity and endocrine disorders in women taking valproate for epilepsy. 861 39

While most studies show a higher body mass in Western women to be positively associated with an increased breast cancer risk in postmenopausal women, they show a negative association in the case of premenopausal women. A review of case-control and cohort studies suggest that such protection applies mainly to obesity in teenage girls, whereas obesity appearing after the teenage years is more likely to be associated with a higher risk of postmenopausal breast cancer. The mechanisms are uncertain. There is evidence that obesity and the components of the Western diet can independently provoke hyperinsulinaemic insulin resistance at puberty, and in adolescent girls this has been related to evidence of abnormal ovarian steroidogenesis and anovulation. This may decrease promotion of mammary carcinogenesis. If however, obesity continues after the teenage years, the higher concentration of insulin-like growth factor 1 (IGF1) associated with hyperinsulinaemia can interact with oestrogen receptors in mammary epithelium to lead to increased proliferative activity. This review postulates that the observed protective effect of early obesity against premenopausal breast cancer is likely to be replaced by an increased risk of postmenopausal breast cancer if obesity continues after the teenage years. The manifestation of breast cancer is merely postponed to an older age. Recent prospective and case-control studies suggest that increased bioavailability of IGF1 is a marker of increased breast cancer risk in premenopausal women. Nutritional intake in early life may programme later activity in the growth hormone-IGF1 axis and influence the progression of transformed cells in mammary tissue. The question remains whether deliberate weight loss can reverse the effects of weight gain.
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PMID:Teenage obesity in relation to breast cancer risk. 982 39

A family of insulin receptor substrate (IRS) proteins mediates the pleiotropic effects of insulin and insulin-like growth factor 1 (IGF-1) on cellular function by recruiting several intracellular signalling networks. Conventional murine knockout strategies have started to reveal distinct physiological roles for the IRS proteins. Deletion of Irs1 produces a mild metabolic phenotype with compensated insulin resistance but also causes marked growth retardation. In contrast, mice lacking IRS-2 display nearly normal growth but develop diabetes owing to a combination of peripheral insulin resistance and beta-cell failure. As well as the classical metabolic events regulated by insulin signalling pathways, studies in lower organisms have implicated insulin/IGF-1 signalling pathways in the control of food intake and reproductive function. Our analysis of IRS-2 knock-out mice shows that female mice are infertile owing to defects in the hypothalamus, pituitary and gonad. IRS-2(-/-) mice have small, anovulatory ovaries with reduced numbers of follicles. Levels of the pituitary hormones luteinizing hormone and prolactin and gonadal steroids are low in these animals. Pituitaries of IRS-2(-/-) animals are decreased in size and contain reduced numbers of gonadotrophs. Additionally, IRS-2(-/-) females display increased food intake and develop obesity, despite elevated leptin levels, suggesting abnormalities in hypothalamic function. Coupled with recent observations that brain-specific deletion of the insulin receptor causes a similar phenotype, these findings implicate IRS signalling pathways in the neuroendocrine regulation of reproduction and energy homeostasis.
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PMID:Insulin receptor substrate proteins and neuroendocrine function. 1149 21

Caloric restriction has been shown to increase longevity in organisms ranging from yeast to mammals. In some organisms, this has been associated with a decreased fat mass and alterations in insulin/insulin-like growth factor 1 (IGF-1) pathways. To further explore these associations with enhanced longevity, we studied mice with a fat-specific insulin receptor knockout (FIRKO). These animals have reduced fat mass and are protected against age-related obesity and its subsequent metabolic abnormalities, although their food intake is normal. Both male and female FIRKO mice were found to have an increase in mean life-span of approximately 134 days (18%), with parallel increases in median and maximum life-spans. Thus, a reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signaling.
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PMID:Extended longevity in mice lacking the insulin receptor in adipose tissue. 1272 May 29

Obesity-induced insulin resistance (IR) is a common problem in humans as well as domestic dogs. It is well-known that this syndrome is associated with many modifications but it is still unclear if the changes are alterations or adaptations. The purpose of this study was to develop obesity-induced IR in dogs, through a long-term overfeeding period, and to explore hormonal and metabolic disturbances associated with the development of this syndrome. Dogs were overfed for 7 months. Body weight increased by 43 +/- 5%, and insulin sensitivity decreased by 44 +/- 5%. Plasma insulin-like growth factor 1 (IGF1), tumour necrosis factor alpha (TNFalpha), and non-esterified fatty acids (NEFA) concentrations progressively increased during the overfeeding period (IGF1: 111 +/- 13 to 266 +/- 32 ng/ml, p < 0.001; TNFalpha: 5 +/- 5 to 134 +/- 41 pg/ml; NEFA: 0.974 +/- 0.094 to 1.590 +/- 0.127 mmol/l, p < 0.05). These metabolic and hormonal impairments are associated with IR, in obese dogs, and could explain, at least in part, the outbreak of this syndrome.
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PMID:Insulin resistance and changes in plasma concentration of TNFalpha, IGF1, and NEFA in dogs during weight gain and obesity. 1505 41


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