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

Obesity is a major risk factor for endometrial cancer, a relationship thought to be largely explained by the prevalence of high estrogen levels in obese women. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed whether insulin and/or insulin-like growth factor-I (IGF-I), a related hormone, are associated with endometrial cancer while accounting for estrogen levels. We therefore conducted a case-cohort study of incident endometrial cancer in the Women's Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. The study involved all 250 incident cases and a random subcohort of 465 subjects for comparison. Insulin, total IGF-I, free IGF-I, IGF-binding protein-3, glucose, and estradiol levels were measured in fasting baseline serum specimens. Cox models were used to estimate associations with endometrial cancer, particularly endometrioid adenocarcinomas, the main histologic type (n = 205). Our data showed that insulin levels were positively associated with endometrioid adenocarcinoma [hazard ratio contrasting highest versus lowest quartile (HR(q4-q1)), 2.33; 95% confidence interval (95% CI), 1.13-4.82] among women not using hormone therapy after adjustment for age and estradiol. Free IGF-I was inversely associated with endometrioid adenocarcinoma (HR(q4-q1), 0.53; 95% CI, 0.31-0.90) after adjustment for age, hormone therapy use, and estradiol. Both of these associations were stronger among overweight/obese women, especially the association between insulin and endometrioid adenocarcinoma (HR(q4-q1), 4.30; 95% CI, 1.62-11.43). These data indicate that hyperinsulinemia may represent a risk factor for endometrioid adenocarcinoma that is independent of estradiol. Free IGF-I levels were inversely associated with endometrioid adenocarcinoma, consistent with prior cross-sectional data.
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PMID:A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. 1839 32

Obesity is a major risk factor for the development and progression of breast cancer. Increased circulating levels of the obesity-associated hormones leptin and insulin-like growth factor-I (IGF-I) and overexpression of the leptin receptor (Ob-R) and IGF-I receptor (IGF-IR) have been detected in a majority of breast cancer cases and during obesity. Due to correlations between increased leptin, Ob-R, IGF-I, and IGF-IR in breast cancer, we hypothesized that molecular interactions may exist between these two signaling pathways. Coimmunoprecipitation and immunoblotting showed that IGF-IR and Ob-R interact in the breast cancer cell lines MDA-MB-231, MCF7, BT474, and SKBR3. Stimulation of cells with IGF-I promoted Ob-R phosphorylation, which was blocked by IGF-IR kinase inhibition. In addition, IGF-I activated downstream signaling molecules in the leptin receptor and IGF-IR pathways. In contrast to IGF-I, leptin did not induce phosphorylation of IGF-IR, indicating that receptor cross-signaling is unidirectional, occurring from IGF-IR to Ob-R. Our results show, for the first time, a novel interaction and cross-talk between the IGF-I and leptin receptors in human breast cancer cells.
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PMID:A novel unidirectional cross-talk from the insulin-like growth factor-I receptor to leptin receptor in human breast cancer cells. 1851 55

Insulin resistance relates to hepatic glucose production (HGP) and hepatic triglyceride content (HTG). Elevation of free fatty acids (FFA) and imbalance of adipocytokines are major mechanisms involved in insulin resistance. Using isolated perfused rat livers we examined metabolic effects of hormones, FFA and leptin. Not only insulin, but also insulin-like growth factor-I similarly decreased epinephrine-induced HGP. Likewise, leptin not only reduced epinephrine-induced HGP, but also decreased fasting HGP by inhibiting gluconeogenesis from lactate. This resulted from the stimulation of the insulin receptor substrate (IRS)-2 pathway and the synthesis of phosphoenolpyruvate carboxykinase, whereas the IRS-1 pathway is inhibited. In dietary-induced obesity, leptin receptors and signalling were downregulated and its cross-talk with insulin signalling was differentially regulated depending on nutritional status. Leptin further increased HTG and intrahepatic FFA. A short-term increase in circulating FFA (palmitate and oleate) augmented lactate uptake, but not HGP. This early effect was paralleled by protein phosphorylation at different sites resulting in impaired insulin signalling.
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PMID:Hepatic glucose production and insulin resistance. 1899 72

The prevalence of obesity, an established risk factor for several types of cancer, has increased steadily over the past several decades in the United States. New targets and strategies for offsetting the effect of obesity on cancer risk are urgently needed. In the present study, we examined the effect of dietary energy balance manipulation on steady-state signaling in multiple epithelial tissues, with a focus on the Akt and mammalian target of rapamycin (mTOR) pathways. For these experiments, male FVB/N and C57BL/6 and female ICR mice were maintained on a control (10 kcal% fat) diet, a diet-induced obesity (DIO; 60 kcal% fat) regimen, or a 30% calorie restriction (CR) regimen for 15 to 17 weeks. Relative to the control group, the DIO regimen increased, whereas CR decreased, circulating insulin-like growth factor-I (IGF-I) as has previously been reported. Western blot analyses showed that the DIO regimen enhanced, whereas CR inhibited, activation of Akt and mTOR, regardless of epithelial tissue or genetic background. In contrast, activation of AMP-activated protein kinase was modulated by dietary energy balance manipulation in the liver but not in the epidermis or dorsolateral prostate. Western blot analyses of epidermal extracts taken from ICR mice also revealed reduced activation of both the IGF-I receptor and epidermal growth factor receptor in CR mice, compared with control mice or mice maintained on the DIO regimen. Taken together, these novel findings suggest that dietary energy balance modulates signaling through cell-surface receptors (i.e., IGF-I receptor and epidermal growth factor receptor), affecting activation of multiple downstream pathways including Akt and mTOR, thus providing important dietary and pharmacologic targets for disrupting the obesity-cancer link.
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PMID:Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues. 1913 37

Appropriate feed intake level would enhance embryo survival. This study investigated the relationship among feed intake level, embryo survival, hormone secretion and mRNA expression. Fifty-four Landrace x Yorkshire crossbred gilts were allotted to three treatment groups of high (H, 2 x maintenance), medium (M, 1.2 x maintenance) and low (L, 0.6 x maintenance) after mating, to study the effect of feed intake levels on embryo survival, hormone secretion and mRNA expression of leptin, obesity receptor (ob-R), signal transducer and activator of transcription-3 (STAT3), DNA methyltransferase 1 (DNMT1), retinol-binding protein 4 (RBP4), fibroblast growth factor receptor 2 (FGFR2) and progesterone receptor (PGR) in embryos. Blood samples and embryos were collected for hormone concentrations determination and gene expression analysis. Slaughter weight, total weight gain and net weight gain were affected (p < 0.05) by dietary treatment. Embryonic survival was 80.23% and 78.45% in M group on days 25 and 35 of pregnancy, respectively, and was greater (p < 0.05) in M than H and L groups. Serum insulin-like growth factor-I and leptin concentrations enhanced (p < 0.05) with the increased feed intake, but progesterone concentrations were lower (p < 0.05) in H than M and L groups and no difference (p > 0.05) between M and L on days 25 and 35 of pregnancy. Real-Time PCR indicated that gene expression pattern of leptin, ob-R, STAT3 and DNMT1 were the highest (p < 0.05) in H group on days 25 and 35 of pregnancy. Transcript expression level of RBP4 and FGFR2 were the highest (p < 0.05) in M group on days 25 and 35 of pregnancy. Significantly higher (p < 0.05) expression of PGR was observed in L group on day 25 and in M group on day 35 of pregnancy. Our data suggest that 1.2 x maintenance feed intake level promoted the appropriate hormone secretion and enhanced genes expression in RBP4, FGFR2 and PGR, and thus resulted in better embryo survival compared with the high and low groups.
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PMID:The level of feed intake affects embryo survival and gene expression during early pregnancy in gilts. 1921 Jun 67

Adiponectin has been reported to regulate systemic insulin sensitivity as a part of a broader control mechanism in energy balance. However, it is not clear whether adiponectin exerts its positive effects on insulin sensitivity equally in a wide range of obesity. We investigated the association of plasma adiponectin concentration with insulin resistance (IR) in a cross-sectional sample of 98 middle-aged premenopausal women with a wide range of obesity. In addition, we studied the relationship between adiponectin, body composition, and blood biochemical and cardiorespiratory fitness variables. Body composition and fat distribution were measured via dual-energy x-ray absorptiometry in normal-weight (NW) (n = 41, body mass index [BMI] < 25 kg/m(2)) and overweight (OW) (n = 57, BMI > or = 25 kg/m(2)) women. Fasting blood samples were obtained; adiponectin, leptin, insulin, glucose, and insulin-like growth factor-I were measured; and IR index was calculated. The IR index from fasting plasma insulin and plasma glucose levels was estimated using the homeostasis model assessment (HOMA), as follows: fasting plasma insulin (in microliter units per milliliter) x fasting plasma glucose (in millimoles per liter)/22.5. Adiponectin was significantly higher (P = .0001) in NW (14.7 +/- 4.7 microg/mL) compared with OW (9.9 +/- 3.1 microg/mL) women. Significant differences (P < .003) in body mass, BMI, percentage of fat mass, fat mass, trunk fat, trunk fat-leg fat ratio, leptin, insulin, and HOMA were also observed between NW and OW groups. Leptin was independently related to plasma adiponectin (beta = -.259, P = .001) in the overall study group. Plasma adiponectin was only related to trunk fat-leg fat ratio (beta = -.242, P = .002) among NW subjects, whereas plasma adiponectin was related to fat-free mass (beta = .182, P = .0001) and HOMA (beta = -.576, P = .002) among OW women. The inverse relationship between adiponectin and leptin concentrations suggests that leptin may be involved in the regulation of adiponectin in middle-aged premenopausal women. Our data also demonstrate that adiponectin may play an important role in sustaining insulin sensitivity only in OW middle-aged premenopausal women.
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PMID:Plasma adiponectin and insulin sensitivity in overweight and normal-weight middle-aged premenopausal women. 1937 86

Quantitative trait loci (QTL) for metabolic and body composition traits were mapped at 7 and 9 wk, respectively, in an F(2) intercross between high-growth and low-growth chicken lines. These lines also diverged for abdominal fat percentage (AFP) and plasma insulin-like growth factor-I (IGF-I), insulin, and glucose levels. Genotypings were performed with 129 microsatellite markers covering 21 chromosomes. A total of 21 QTL with genomewide level of significance were detected by single-trait analyses for body weight (BW), breast muscle weight (BMW) and percentage (BMP), AF weight (AFW) and percentage (AFP), shank length (ShL) and diameter (ShD), fasting plasma glucose level (Gluc), and body temperature (T(b)). Other suggestive QTL were identified for these parameters and for plasma IGF-I and nonesterified fatty acid levels. QTL controlling adiposity and Gluc were colocalized on GGA3 and GGA5 and QTL for BW, ShL and ShD, adiposity, and T(b) on GGA4. Multitrait analyses revealed two QTL controlling Gluc and AFP on GGA5 and Gluc and T(b) on GGA26. Significant effects of the reciprocal cross were observed on BW, ShD, BMW, and Gluc, which may result from mtDNA and/or maternal effects. Most QTL regions for Gluc and adiposity harbor genes for which alleles have been associated with increased susceptibility to diabetes and/or obesity in humans. Identification of genes responsible for these metabolic QTL will increase our understanding of the constitutive "hyperglycemia" found in chickens. Furthermore, a comparative approach could provide new information on the genetic causes of diabetes and obesity in humans.
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PMID:QTL for several metabolic traits map to loci controlling growth and body composition in an F2 intercross between high- and low-growth chicken lines. 1953 76

Growth hormone (GH) is the most important hormonal regulator of postnatal longitudinal growth in man. In adults GH is no longer needed for longitudinal growth. Adults with growth hormone deficiency (GHD) are characterised by perturbations in body composition, lipid metabolism, cardiovascular risk profile and bone mineral density. It is well established that adult GHD usually is accompanied by an increase in fat accumulation and GH replacement in adult patients with GHD results in reduction of fat mass and abdominal fat mass in particular. It is also recognized that obesity and abdominal obesity in particular results in a secondary reduction in GH secretion and subnormal insulin-like growth factor-I (IGF-I) levels. The recovery of the GH IGF-I axis after weight loss suggest an acquired defect, however, the pathophysiologic role of GH in obesity is yet to be fully understood. In clinical studies examining the efficacy of GH in obese subjects very little or no effect are observed with respect to weight loss, whereas GH seems to reduce total and abdominal fat mass in obese subjects. The observed reductions in abdominal fat mass are modest and similar to what can be achieved by diet or exercise interventions.
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PMID:Obesity, growth hormone and weight loss. 1972 58

Body mass index, as an approximation of body adiposity, is associated with increased risk of several common and less common malignancies in a sex- and site-specific manner. These findings implicate sex- and cancer site-specific biological mechanisms underpinning these associations, and it is unlikely that there is a "one system fits all" mechanism. Three main candidate systems have been proposed-insulin and the insulin-like growth factor-I axis, sex steroids, and adipokines-but there are shortfalls to these hypotheses. In this review, three novel candidate mechanisms are proposed: obesity-induced hypoxia, shared genetic susceptibility, and migrating adipose stromal cells. While public health policies aimed at curbing the underlying causes of the obesity epidemic are being implemented, there is a parallel need to better understand the biological processes linking obesity and cancer as a prerequisite to the development of new approaches to prevention and treatment.
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PMID:Biological mechanisms linking obesity and cancer risk: new perspectives. 1982 17

Among the mechanisms implicated in the tumor-promoting effects of obesity, signaling by insulin-like growth factor-I (IGF-I) and insulin has received considerable attention. However, the emerging realization that obesity is associated with chronic inflammation has prompted other consideration of how the IGF-I axis may participate in cancer progression. In the present study, we used two mouse models of chronic (LID) and inducible (iLID) igf-1 gene deficiency in the liver to investigate the role of IGF-I in regulating the host microenvironment and colorectal carcinoma growth and metastasis in obese mice. Obese mice had a heightened inflammatory response in the liver, which was abolished in mice with chronic IGF-I deficiency (LID). In control animals changes to the hepatic microenvironment associated with obesity sustained the presence of tumor cells in the liver and increased the incidence of hepatic metastases after intrasplenic/portal inoculation of colon carcinoma cells. These changes did not occur in LID mice with chronic IGF-1 deficiency. In contrast, these changes occurred in iLID mice with acute IGF-1 deficiency, in the same manner as the control animals, revealing a fundamental difference in the nature of the requirement for IGF-1 on tumor growth and metastasis. In the setting of obesity, our findings imply that IGF-1 is critical to activate and sustain an inflammatory response in the liver that is needed for hepatic metastasis, not only through direct, paracrine effect on tumor cell growth, but also through indirect effects involving the tumor microenvironment.
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PMID:Insulin-like growth factor-I regulates the liver microenvironment in obese mice and promotes liver metastasis. 2004 72


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