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

Obesity and related metabolic abnormalities, including insulin resistance, are risk factors for hepatocellular carcinoma in non-alcoholic steatohepatitis as well as in chronic viral hepatitis. Branched-chain amino acids (BCAA), which improve insulin resistance, inhibited obesity-related colon carcinogenesis in a rodent model, and also reduced the incidence of hepatocellular carcinoma in obese patients with liver cirrhosis. In the present study, we determined the effects of BCAA on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in obese C57BL/KsJ-db/db (db/db) mice with diabetes mellitus. Male db/db mice were given tap water containing 40 ppm DEN for an initial 2 weeks and thereafter they received a basal diet containing 3.0% of BCAA or casein, which served as a nitrogen content-matched control of BCAA, throughout the experiment. Supplementation with BCAA significantly reduced the total number of foci of cellular alteration, a premalignant lesion of the liver, and the expression of insulin-like growth factor (IGF)-1, IGF-2, and IGF-1 receptor in the liver when compared to the casein supplementation. BCAA supplementation for 34 weeks also significantly inhibited both the development of hepatocellular neoplasms and the proliferation of hepatocytes in comparison to the basal diet or casein-fed groups. Supplementation with BCAA improved liver steatosis and fibrosis and inhibited the expression of alpha-smooth muscle actin in the DEN-treated db/db mice. The serum levels of glucose and leptin decreased by dietary BCAA, whereas the value of the quantitative insulin sensitivity check index increased by this agent, indicating the improvement of insulin resistance and hyperleptinemia. In conclusion, oral BCAA supplementation improves insulin resistance and prevents the development of liver tumorigenesis in obese and diabetic mice.
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PMID:Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. 1990 67

Dietary calcium inhibits adiposity, and a key underlying mechanism is suppression of calcitriol, which modulates Ca(2+) signaling and mitochondrial uncoupling in adipocytes. We demonstrated that calcitriol directly regulates adipocyte 11beta-HSD-1 expression and cortisol production in human adipocytes in vitro and dietary calcium inhibits visceral adipose tissue 11beta-HSD-1 expression in mice, indicating an interaction of calcitriol and cortisol in obesity. Consequently, we have evaluated the gene expression profile of human subcutaneous adipocytes treated with calcitriol and/or cortisone. Data analysis demonstrated significant calcitriol modulation of gene expression toward inhibition of the adipocyte apoptosis (e.g., VEGF and STC-2) and promotion of adipocyte proliferation (e.g., IGF-1 and IGF-1R). Calcitriol also up-regulated oxidative stress and inflammatory genes such as NOX-4 and TLR-3. The calcitriol/cortisone combination resulted in significant additional up-regulation of 11beta-HSD-1 and down-regulation of adiponectin expression, while cortisone exerted little independent effect in the absence of calcitriol. Overall, calcitriol stimulated a pattern of adipocyte gene expression which favored adipocyte proliferation, oxidative and inflammatory stress and visceral adiposity, and these effects were amplified in the presence of cortisone; however, this conclusion must be tempered by the adipocyte source (subcutaneous) and requires confirmation in visceral adipocytes.
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PMID:Role of calcitriol and cortisol on human adipocyte proliferation and oxidative and inflammatory stress: a microarray study. 1991 13

Leptin, a pleiotropic hormone regulating food intake and metabolism, plays an important role in the regulation of inflammation and immunity. We previously demonstrated that serum leptin levels are profoundly increased in mice which received azoxymethane (AOM) and dextran sulfate sodium (DSS) as tumor-initiator and -promoter, respectively, in a colon carcinogenesis model. In this study, we attempted to address underlying mechanism whereby leptin is up-regulated in this rodent model. Five-week-old male ICR mice were given a single intraperitoneal injection of AOM (week 0), followed by 1% DSS in drinking water for 7 days. Thereafter, the weights of visceral fats and the serum concentration of leptin were determined at week 20. Of interest, the relative epididymal fat pad and mesenteric fat weights, together with serum leptin levels in the AOM and/or DSS-treated mice were markedly increased compared to that in untreated mice. In addition, leptin protein production in epididymal fat pad with AOM/DSS-treated mice was 4.7-fold higher than that of control. Further, insulin signaling molecules, such as protein kinase B (Akt), S6, mitogen-activate protein kinase/extracellular signaling-regulated kinase 1/2, and extracellular signaling-regulated kinase 1/2, were concomitantly activated in epididymal fat of AOM/DSS-treated mice. This treatment also increased the serum insulin and IGF-1 levels. Taken together, our results suggest that higher levels of serum insulin and IGF-1 promote the insulin signaling in epididymal fat and thereby increasing serum leptin, which may play an crucial role in, not only obesity-related, but also -independent colon carcinogenesis.
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PMID:Increased visceral fat mass and insulin signaling in colitis-related colon carcinogenesis model mice. 1993 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

Studies over the last several years have revealed important roles of the body fat content, caloric intake and nutrition, insulin/IGF-1 signaling systems, and pathways involved in oxidative stress and control of protein acetylation on life span. Although the discovery of longevity genes supports the concept that life span is genetically determined, adipose tissue seems to be a pivotal organ in the aging process and in the determination of life span. Leanness and caloric restriction have been shown to increase longevity in organisms ranging from yeast to mammals. Increased longevity in mice with a fat-specific disruption of the insulin receptor gene (FIRKO) suggests that reduced adiposity, even in the presence of normal or increased food intake, leads to an extended life span. Reduced fat mass has an impact on longevity in a number of other model organisms. In Drosophila, a specific reduction in the fat body through overexpression of forkhead type transcription factor (dFOXO) extends life span. Sirtuin 1 (SIRT1), the mammalian ortholog of the life-extending yeast gene silent information regulator 2 (SIR2), was proposed to be involved in the molecular mechanisms linking life span to adipose tissue. Moreover, in the control of human aging and longevity, one of the striking physiological characteristics identified in centenarians is their greatly increased insulin sensitivity even compared with younger individuals. On the other hand, overweight and obesity seem to be associated with decreased life span in humans. In addition, it was recently shown that modifiable risk factors during the later years of life, including smoking, obesity, and hypertension, are associated not only with lower life expectancy, but also with poor health and function during older age. There is growing evidence that the effect of reduced adipose tissue mass on life span could be due to the prevention of obesity-related metabolic disorders including type 2 diabetes and atherosclerosis.
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PMID:Fat tissue and long life. 2005 78

GH and IGF-1 play an important role in the regulation of metabolism and body composition. In patients with uncontrolled acromegaly, cardiovascular morbidity and mortality are increased but are supposed to be normalised after biochemical control is achieved. We aimed at comparing body composition and the cardiovascular risk profile in patients with controlled acromegaly and controls. A cross-sectional study. We evaluated anthropometric parameters (height, weight, body mass index (BMI), waist and hip circumference, waist to height ratio) and, additionally, cardiovascular risk biomarkers (fasting plasma glucose, HbA1c, triglycerides, total cholesterol, HDL, LDL, and lipoprotein (a), in 81 acromegalic patients (58% cured) compared to 320 age- and gender-matched controls (ratio 1:4), sampled from the primary care patient cohort DETECT. The whole group of 81 acromegalic patients presented with significantly higher anthropometric parameters, such as weight, BMI, waist and hip circumference, but with more favourable cardiovascular risk biomarkers, such as fasting plasma glucose, total cholesterol, triglycerides and HDL levels, in comparison to their respective controls. Biochemically controlled acromegalic patients again showed significantly higher measurements of obesity, mainly visceral adiposity, than age- and gender-matched control patients (BMI 29.5 +/- 5.9 vs. 27.3 +/- 5.8 kg/m(2); P = 0.020; waist circumference 100.9 +/- 16.8 vs. 94.8 +/- 15.5 cm; P = 0.031; hip circumference 110.7 +/- 9.9 vs. 105.0 +/- 11.7 cm; P = 0.001). No differences in the classical cardiovascular biomarkers were detected except for fasting plasma glucose and triglycerides. This effect could not be attributed to a higher prevalence of type 2 diabetes mellitus in the acromegalic patient group, since stratified analyses between the subgroup of patients with acromegaly and controls, both with type 2 diabetes mellitus, revealed that there were no significant differences in the anthropometric measurements. Biochemically cured acromegalic patients pertain an adverse anthropometric risk profile, mainly because of elevated adiposity measurements, such as BMI, waist and hip circumference, compared to an age- and gender-matched primary care population.
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PMID:Adverse anthropometric risk profile in biochemically controlled acromegalic patients: comparison with an age- and gender-matched primary care population. 2013 Nov

The relationship between obesity, metabolic syndrome, diabetes and cancer has been recognized for many years. Multiple studies conducted in the last 20 years have identified molecular mechanisms responsible for this phenomenon. Elucidation of the important role of insulin, IGF receptor, mTOR and AMP-activated protein kinase in breast cancer biology has led to the development and subsequent clinical evaluation of novel targeted therapies, including IGF-1 receptor-specific antibodies or tyrosine kinase inhibitors and inhibitors of mTOR. There is also a growing interest in the use of metformin, which has been shown to possess antitumor activity resulting from activation of AMP-activated protein kinase and subsequent inhibiton of mTOR, as well as from decreased circulating insulin levels. Metformin has been shown to inhibit proliferation, invasion and angiogenesis of neoplastic cells and to overcome resistance of breast cancer to chemotherapy, hormonal therapy and HER2 inhibition. Recently, metformin has been demonstrated to inhibit breast cancer stem cell growth and to synergize with chemotherapy in suppression of tumor growth and prolongation of survival of breast tumor-bearing animals. Several currently ongoing Phase II and III clinical studies are evaluating the therapeutic efficacy of metformin in the treatment of early and advanced breast cancer patients.
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PMID:Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin. 2046 5

With an increasing spectrum of indications for growth hormone (GH), knowledge of the short- and long-term safety of this treatment is essential. In this chapter we review the main adverse effects that have been demonstrated or discussed after long-term GH treatment in children. It is well recognized that plasma insulin concentrations increase during GH treatment. The incidence of type 2 diabetes is raised during GH treatment, especially in subjects with other risk factors. Recommendations include assessing glucose tolerance by measuring plasma glucose and HbA1c before and during treatment. There is no consensus on the indications for insulin measurement and/or oral glucose tolerance tests. Other recognized short-term complications of GH treatment include pseudo-tumour cerebri, otitis media (Turner syndrome), and orthopaedic problems such as worsening of scoliosis and slipped femoral epiphysis. There are reports of sudden death within the first 6 months of treatment in children with Prader-Willi syndrome, mostly associated with severe obesity. Large cohort follow-up studies suggest that children treated with GH following childhood cancer treatment do not have a greater number of relapses, but there may be a higher incidence of second primary tumours in the early years of GH therapy. A cohort treated with human pituitary GH showed a higher incidence of tumours, and a GH effect on tumorigenesis has been seen in follow-up studies of acromegaly raising the question of whether de novo cancer risk may be increased. A new prospective pan-European safety surveillance study (SAGhE) has been launched to address these essential questions. The role of monitoring the IGF-1 response (total or free concentrations) to GH treatment to predict long-term safety is unclear at present. Attempts to target IGF-1 levels within the normal range may result in the use of excessive doses of GH. In general, higher dosage GH regimens may be associated with supraphysiological IGF-1 levels.
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PMID:Safety of recombinant human growth hormone. 2052 16

Obesity is highly associated with an increased risk of serious health conditions including hypertension, cardiovascular disease, diabetes, and cancer. Changes in redox status with increased oxidative stress have been linked with obesity. Previous studies have shown that administration of the antioxidant Tempol in the food of mice prevents obesity, causing significant weight loss without toxicity. To gain a better understanding of the molecular mechanism(s) underlying this effect, the influence of Tempol on the differentiation of mouse 3T3-L1 preadipocytes was studied. Tempol inhibited differentiation of 3T3-L1 cells, resulting in a reduction in cellular lipid storage, down-regulation of protein levels of key adipogenesis transcription factors (PPARgamma and PPARalpha), down-regulation of prolyl hydroxylase, and up-regulation of HIF-1alpha. Mice on a Tempol diet demonstrated reduced systemic levels of IGF-1, in qualitative agreement with in vitro observations in 3T3-L1 cells, which also showed lower IGF-1 levels as a result of Tempol treatment. These results show that treatment of 3T3-L1 cells with Tempol inhibits the expression of key adipogenesis factors, adipose differentiation, and lipid storage and may underlie, at least in part, some of the in vivo effects of Tempol on body weight.
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PMID:Inhibition of adipogenesis by Tempol in 3T3-L1 cells. 2056 4

Obesity results in increased circulating levels of specific adipokines, which are associated with colon cancer risk. The disease state is associated with increased leptin, insulin, IGF-1, and IL-6. Conversely, adiponectin levels are decreased in obese individuals. Previously, we demonstrated adipokine-enhanced cell proliferation in preneoplastic, but not normal, colon epithelial cells, demonstrating a differential effect of adipokines on colon cancer progression in vitro. Using a model of late stage carcinoma cancer cell, namely murine MC-38 colon carcinoma cells, we compared the effect of obesity-associated adipokines (leptin, insulin, IGF-1, and IL-6) on MC-38 cell proliferation and determined whether adiponectin (full length or globular) could modulate adipokine-induced cell proliferation. We show that insulin and IL-6, but not leptin and IGF-1, induce proliferation in MC-38 cells. Adiponectin treatment of MC-38 cells did not inhibit insulin-induced cell proliferation but did inhibit IL-6-induced cell proliferation by decreasing STAT-3 phosphorylation and activation. Nitric oxide (NO) production was increased in MC-38 cells treated with IL-6; co-treatment with adiponectin blocked IL-6-induced iNOS and subsequent NO production. These data are compared to previously reported findings from our laboratory using the YAMC (model normal colon epithelial cells) and IMCE (model preneoplastic) cells. The cell lines are utilized to construct a model summarizing the hormonal consequences of obesity and the impact on the differential regulation of colon epithelial cells along the continuum to carcinoma. These data, taken together, highlight mechanisms involved in obesity-associated cancers and may lead to potential-targeted therapies.
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PMID:Adipokine regulation of colon cancer: adiponectin attenuates interleukin-6-induced colon carcinoma cell proliferation via STAT-3. 2056 47


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