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)

Ablation of the hypothalamic peptide, melanin-concentrating hormone (MCH), leads to a lean phenotype and resistance to diet-induced obesity. Observation of MCH(-/-) mice at older ages suggested that these effects persist in mice >1 year old. Leanness secondary to caloric restriction is known to be associated with improved glucose tolerance as well as an overall increase in life span. Because the MCH(-/-) model represents leanness secondary to increased energy expenditure rather than caloric restriction, we were interested in determining whether this model of leanness would be associated with beneficial metabolic effects at older ages. To assess the effects of MCH ablation over a more prolonged period, we monitored male and female MCH(-/-) mice up to 19 months. The lean phenotype of MCH(-/-) mice persisted over the duration of the study. At 19 months, MCH(-/-) male and female mice weighed 23.4 and 30.8% less than their wild-type counterparts, a result of reduced fat mass in MCH(-/-) mice. Aged MCH(-/-) mice exhibited better glucose tolerance and were more insulin sensitive compared with wild-type controls. Aging-associated decreases in locomotor activity were also attenuated in MCH(-/-) mice. We also evaluated two molecules implicated in the pathophysiology of aging, p53 and silent inflammatory regulator 2 (Sir2). We found that expression of the tumor suppressor protein p53 was higher in MCH(-/-) mice at 9 and 19 months of age. In contrast, expression of Sir2 was unchanged. In aggregate, these findings suggest that MCH ablation improves the long-term outcome for several indicators of the aging process.
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PMID:MCH-/- mice are resistant to aging-associated increases in body weight and insulin resistance. 1644 77

We hypothesize that the peroxisome proliferator-activated receptor-gamma (PPARgamma) is associated with colorectal cancer given its association with insulin, diabetes, obesity, and inflammation. In this study, we evaluated the association between colorectal cancer and specific tumor mutations and the Pro12Ala (P12A) PPARgamma polymorphism. We also evaluated interactions between the PPARgamma gene and other insulin-related genes and use of aspirin and non-steroidal anti-inflammatory drug use. Data were available from 1,577 cases of colon cancer that were matched to 1,971 population-based controls and 794 cases of rectal cancer that were matched to 1,001 population-based controls. Colon tumors from the case subjects were evaluated for p53 and Ki-ras mutations and microsatellite instability (MSI). Insulin-related genes evaluated were the Bsm1, polyA, and Fok1 polymorphisms of the VDR gene; the G972R IRS1 polymorphism; the G1057D IRS2 polymorphism; the 19CA repeat polymorphism of the IGF1 gene; and the -200A>C IGFBP3 polymorphism. The odds ratio (OR) between the PA/AA genotypes and proximal tumors was 0.83 (95% CI: 0.69-1.01); for distal tumors was 1.00 (95% CI: 0.83-1.21); and for rectal tumors was 1.04 (95% CI: 0.86-1.25). Evaluation of specific types of tumor mutations showed that colon cancer cases with the PA or AA genotypes were less likely to have p53 tumor mutations (OR 0.78; 95% CI: 0.62-0.99), specifically transition mutations (OR 0.74; 95% CI: 0.56-0.97). Colon cancer cases also were less likely to have a tumor with MSI if they had the PA or AA PPARgamma genotype (OR 0.68; 95% CI: 0.47-0.98); differences in Ki-ras mutations were not seen in colon tumors by PPARgamma genotype. Those who did not take ibuprofen-type drugs and had the PA or AA genotypes were at a significantly greater risk of rectal cancer (OR 2.11; 95% CI: 1.52-2.92; p interaction 0.03) than people with the PP genotype regardless of ibuprofen-type drug use. There was a significant interaction between the -200A>C IGFBP3 polymorphism and the Pro12Ala PPARgamma polymorphism and risk of colon cancer (p for interaction = 0.02) with individuals being at significantly lower risk if they had both the CC IGFBP3 genotype and the PA/AA PPARgamma genotype. For rectal cancer there was a significant interaction between the Bsm1/polyA polymorphisms (p = 0.001) of the VDR gene and the PA/AA Pro12Ala PPARgamma polymorphism with the highest risk group being those with both the PA/AA Pro12Ala PPARgamma and the BB/SS VDR genotypes. These data suggest that PPARgamma may be associated with many aspects of colorectal cancer including insulin- and inflammation-related mechanisms.
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PMID:PPARgamma and colon and rectal cancer: associations with specific tumor mutations, aspirin, ibuprofen and insulin-related genes (United States). 1648 31

Gallbladder cancer is a common hepato-biliary malignancy with poor prognosis. The main associated risk factors identified so far include cholelithiasis (especially mixed gall stone), chronic infections of the gallbladder, obesity, reproductive factors, diet, hepato-biliary anamolies, and environmental exposure to specific chemicals. Genetic and molecular predisposing factors have also been described. This article reviews the association of chronic infection and gallbladder cancer. Most of the studies have shown a good association of mixed bacterial and Salmonella infections in the carcinogenesis of cancer gallbladder especially in the area of high endemicity of typhoid. Bacterial degradation of bile and chronic inflammation may also play some role in the carcinogenic process. Mutations in multiple tumor suppressor gene and oncogenes (P53 and K-ras) have also been found in a few studies. This review seeks to bring out many hidden infective etiological aspects of the pathogenesis of gallbladder cancer. Review of the entire published literature suggests a need for further studies for better understanding of the disease.
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PMID:Infection as a risk factor for gallbladder cancer. 1672 47

Obesity has been recognized as a risk factor for breast cancer. Adipocyte-derived leptin may play as a paracrine regulator on the growth of breast cancer cells. Expression of both leptin and its OB-Rb receptor was detected in human breast cancer ZR-75-1 cells and further induced by leptin, suggesting that both expression and message mediation of leptin were autoregulated by itself. With cell counting and MTT assay, we had observed leptin stimulated ZR-75-1 growth in dose- and time-dependent manners. To study what steps of cell cycle progression leptin may involve in, we analyzed cell-cycle profile with flow cytometric analysis, mRNA and protein expressions of four cell-cycle regulators with RT-PCR and Western blotting analysis. Under the treatment of leptin, the G1 arrest of cells was reduced accompanied with up-regulation of G1 phase-specific cyclin D1 and proto-oncogene c-Myc, but down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and tumor suppressor p53. Furthermore, JAK2 inhibitor AG490, PI3K/Akt inhibitor Wortmannin, and MEK/ERK1/2 inhibitor PD98059 were efficiently prevented leptin-promoted cell growth. Effect of cooperation between leptin and estrogen on ZR-75-1 growth had been observed. Collectively, the results showed that the proliferative effect of leptin on ZR-75-1 was associated with the up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21(WAF1/CIP1) plausibly through a hypothesized JAK2-PI3K/Akt-MEK/ERK pathway. The leptin- and OB-Rb-expressing capability of ZR-75-1 created a possible autocrine control of leptin, in which signal could be effectively amplified by itself, on cell growth.
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PMID:Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. 1675 79

Transcription factors (TFs), which play crucial roles in the regulation of gene expression in the human genome, are highly regulated by a variety of mechanisms. A single extracellular stimulus can trigger multiple signaling pathways, and these in turn can activate multiple TFs to mediate the inducible expression of target genes. Alterations in the activities of TFs are often associated with human diseases, such as altered activating factor 1, estrogen receptor, and p53 function in cancer, nuclear factor kappaB in inflammatory diseases, and peroxisome proliferator-activated receptor gamma in obesity. A systematic assay for profiling the activation of TFs will aid in elucidating the mechanisms of TF activation, reveal altered TFs associated with human diseases, and aid in developing assays for drug discovery. Here, we developed a 24-plex fluorescent microsphere-based TF activation assay system with a 96-well plate format. The assay system enabled high-throughput profiling of the DNA binding activity of TFs in multiple samples with high sensitivity.
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PMID:Development of a fluorescent microsphere-based multiplexed high-throughput assay system for profiling of transcription factor activation. 1683 34

Obesity is typically associated with increased tumor susceptibility, whereas caloric restriction, a regimen resulting in leanness, inhibits carcinogenesis. The link between adiposity and malignancies suggests that adipose tissue may influence carcinogenesis. An adipose tissue hormone, leptin, could be procarcinogenic because it stimulates proliferation in various tissues and tumor cell lines. Leptin may contribute to the correlation between adiposity and malignancies as its levels are usually increased in obese subjects and reduced by caloric restriction. We hypothesized that leptin deficiency, despite obesity, would inhibit carcinogenesis in leptin-null ob/ob mice and tested this hypothesis in two models: (a) two-stage skin carcinogenesis initiated by 7,12-dimethylbenz(a)anthracene and promoted by phorbol 12-myristate 13-acetate (PMA) and (b) p53 deficiency. Contrary to a typical association between obesity and enhanced carcinogenesis, obese ob/ob mice developed induced skin papillomas and spontaneous p53-deficient malignancies, mostly lymphomas, similarly to their lean littermates. Surprisingly, lipodystrophic (ZIP) mice that had very little both adipose tissue and leptin were highly susceptible to carcinogenesis. Hyperphagia, hyperinsulinemia, and hyperglycemia are unlikely to have contributed significantly to the enhancement of carcinogenesis in ZIP mice because similarly hyperphagic, hyperinsulinemic, and hyperglycemic ob/ob mice had normal susceptibility to carcinogenesis. Our data suggest that, in contrast to a well-known correlation between obesity and cancer, the direct effect of adipose tissue may rather be protective.
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PMID:Susceptibility to induced and spontaneous carcinogenesis is increased in fatless A-ZIP/F-1 but not in obese ob/ob mice. 1695 Dec 7

The target of rapamycin (TOR) pathway regulates ribosome biogenesis, protein synthesis, nutrient import, autophagy and cell cycle progression. After 30 years of concentrated attention, how TOR controls these processes is only now beginning to be understood. Recent advances have identified a wide array of TOR inputs, including amino acids, oxygen, ATP and growth factors, as well the regulatory proteins that facilitate their effects on TOR. Such proteins include AMPK, Rheb and the tumor suppressors LKB1, p53, and Tsc1/2. It has only recently been appreciated that TOR resides in two distinct signaling complexes with differing regulatory roles, only one of which is rapamycin-sensitive, thus opening a new avenue of inquiry into TOR function. Finally, TOR appears to regulate feeding behavior by facilitating communication between organ systems, and is thus implicated in the regulation of glucose and fat homeostasis, and possibly diabetes and obesity. TOR thus functions to coordinate growth-permitting inputs with growth-promoting outputs on both a cellular and an organismal level.
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PMID:Thinking globally and acting locally with TOR. 1704 29

Earlier studies indicated that high dietary fat and obesity are associated with an increased risk of cancer at several organ sites in experimental animals and in humans. In a recent study we found that voluntary running wheel exercise decreased body fat and inhibited ultraviolet B light (UVB)-induced carcinogenesis in the epidermis of SKH-1 mice. In the present study we demonstrate that voluntary running wheel exercise stimulated UVB-induced apoptosis in the epidermis by a p53-independent mechanism, and voluntary exercise also stimulated apoptosis in UVB-induced tumors in tumor-bearing mice. Exercise had no effect in non-UVB-treated epidermis or in areas of the epidermis away from tumors in tumor-bearing mice. In addition, we found that removal of the parametrial fat pads (partial lipectomy) 2 weeks before UVB irradiation enhanced UVB-induced apoptosis. The results of our studies suggest that fat cells secrete substances that inhibit apoptosis in cells with DNA damage and possibly also in tumors. Our results help explain why exercise or various dietary regimens that decrease tissue fat inhibit carcinogenesis.
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PMID:Stimulatory effect of voluntary exercise or fat removal (partial lipectomy) on apoptosis in the skin of UVB light-irradiated mice. 1706 Jun 38

The same dietary component, such as fat or phytochemicals in plant foods, can have an opposite effect on breast cancer risk if exposed in utero through a pregnant mother or at puberty. Dietary exposures during pregnancy often have similar effects on breast cancer risk among mothers and their female offspring. High fat intake and obesity are illustrative examples: excessive pregnancy weight gain that increases high birth weight is associated with increased breast cancer risk among mothers and daughters. High body weight during childhood is inversely linked to later breast cancer risk. The main reason why the age when dietary exposures occur determines their effect on breast cancer risk likely reflects the extensive programming of the mammary gland during fetal life and subsequent reprogramming at puberty and pregnancy. Programming is a series of epigenetic/transcriptional modifications in gene expression that can be influenced by changes in the hormonal environment induced, for example, by diet. Because epigenetic modifications are inherited by daughter cells, they can persist throughout life if they occur in mammary stem cells or uncommitted mammary myoepithelial or luminal progenitor cells. Our results indicate that the estrogen receptor (ER), mitogen-activated protein kinase (MAPK), and the tumor suppressors BRCA1, p53, and caveolin-1 are among the genes affected by diet-induced alterations in programming/reprogramming. Consequently, mammary gland morphology may be altered in a manner that increases or reduces susceptibility to malignant transformation, including an increase/reduction in cell proliferation, differentiation, and survival, or in the number of terminal end buds (TEBs) or pregnancy-induced mammary epithelial cells (PI-MECs) that are the sites where breast cancer is initiated. Thus, dietary exposures during pregnancy and puberty may play an important role in determining later risk by inducing epigenetic changes that modify vulnerability to breast cancer.
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PMID:Timing of dietary estrogenic exposures and breast cancer risk. 1726 53

Overexpression of fatty acid synthase (FASN), a key enzyme for de novo lipogenesis, is observed in many cancers including colorectal cancer and is associated with poor clinical outcomes. Cellular FASN expression is physiologically upregulated in a state of energy excess. Obesity and excess energy balance have been known to be risk factors for colorectal cancer. High degree of microsatellite instability (MSI-H) is a distinct phenotype in colorectal cancer, associated with CpG island methylator phenotype (CIMP). Previous data suggest that obesity or altered energy balance may potentially modify risks for MSI-H cancers and microsatellite stable (MSS) cancers differently. However, the relationship between MSI and FASN overexpression has not been investigated. Using 976 cases of population-based colorectal cancer samples from 2 large prospective cohort studies, we correlated FASN expression (by immunohistochemistry) with MSI, KRAS and BRAF mutations, p53 expression (by immunohistochemistry), and CIMP status [determined by MethyLight for 8 CIMP-specific gene promoters including CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1]. Marked (2+) FASN overexpression was observed in 110 (11%) of the 976 tumors and was significantly more common in MSI-H tumors (21% [28/135]) than MSI-low (5.6% [4/72], P = .004) and MSS tumors (11% [72/678], P = .001). The association between FASN overexpression and MSI-H persisted even after stratification by CIMP status. In contrast, FASN overexpression was not correlated with CIMP after stratification by MSI status. Fatty acid synthase overexpression was not significantly correlated with sex, tumor location, p53, or KRAS/BRAF status. In conclusion, FASN overexpression in colorectal cancer is associated with MSI-H, independent of CIMP status.
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PMID:Fatty acid synthase overexpression in colorectal cancer is associated with microsatellite instability, independent of CpG island methylator phenotype. 1735 Jun 69


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