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)

Adeno-associated viral (AAV) vectors are derived from a nonpathogenic, replication-deficient virus with a small (~4.7-kb) single-stranded DNA genome. AAV vectors are devoid of viral-coding sequences and may efficiently transfer genes to nondividing cells such as muscle fibers or hepatocytes following in vivo transduction. Recombinant AAV can be administered to skeletal muscle of experimental animals and, as recently documented in a Phase I clinical trial, to humans at high vector doses without local or systemic toxicity (8,9). The potential of the vector to activate cytotoxic T lymphocytes is greatly reduced compared with some other viral vectors, thereby reducing the risk of inflammation at the site of gene transfer (7,10,11). Sustained expression of therapeutic transgenes such as coagulation factor IX (F.IX), erythropoietin, leptin, insulin-like growth factor (IGF), sarcoglycans, mini-dystrophin genes, alpha1-antitrypsin, and others have been demonstrated (2,12-18). Efficient gene transfer to myofibers by intramuscular (im) injection has been shown in several species including mice, hamsters, dogs, and nonhuman primates (6-8,13,19). These studies resulted in various levels of correction of the disease phenoypes in small and large animal models of hemophilia B (F.IX deficiency), muscular dystrophy, obesity, age-related atrophy, and beta-thalassemia (8,12,13,15,17,18,20-25).
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PMID:AAV-mediated gene transfer to skeletal muscle. 1497 May 92

The rapid increase in the prevalence of obesity in the last decade indicates a need for effective treatment programs. We conducted a short-term, repeated-measures, clinical-outcome trial in three groups of children and adolescents in two different locations. Two cohorts (n=34) were enrolled in a 36-wk multi-disciplinary weight-management program at the Children's Hospital of New Orleans. One cohort (n=16) was enrolled in a similar intervention at the General Clinical Research Center (GCRC) at the Medical Center of Louisiana for a 10-wk summer weight-loss program. Subjects were offered a protein-sparing modified fast (PSMF) diet (600-800 kcal/d; 2 g protein/kg body weight), followed by a balanced hypocaloric diet, and they participated in behavior-modification sessions and a moderate-intensity (45-55% volume of oxygen consumed at maximal effort [VO(2)max]), progressive exercise program. The following parameters were examined at baseline, 10 wk, and 36 wk (cohort 1 only): Weight, height, percentage of ideal body weight (%IBW), relative body fat (%fat), fat free body (FFB) mass, estimated VO(2)max mL/kg min(BW) [adjusted for body weight]), blood chemistries, lipid profiles (total cholesterol [TC], triglycerides [TG], low-density lipoprotein [LDL], high-density lipoprotein [HDL], and insulin-like growth factor-1 [IGF-1]). All three groups experienced significant decreases in weight, %IBW and %fat at 10 wk. The weight loss was maintained at 26 wk in cohorts 1 and 2, and at 36 wk in cohort 1. There were no significant decreases in height velocity during the study. In addition, measures of estimated VO(2)max mL/kg/min(BW) and IGF-1 parameters were significantly greater at 10 wk compared to baseline. Measures of TC, TG, and LDL were significantly lower at 10 wk, with no significant changes noted in HDL. We conclude that a multi-disciplinary weight-management program, including PSMF, behavior modification, and exercise, provides an effective method of treatment for obesity in children and adolescents. Long-term, randomized, and controlled clinical trials are needed to confirm the results of this preliminary, short-term observation.
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PMID:Recent advances in the treatment of childhood obesity. 1501 39

Physical activity has been shown to reduce risk of colon cancer. Some studies have shown site-specific associations while others have not. The inverse association between physical activity and colon cancer is consistent although only 7 of 13 studies that have collected both colon and rectal cancer data in the same manner report reduced risk for rectal cancer; four of these studies detected statistically significant inverse associations. The frequency, duration and intensity of activity are important components of a public health message to reduce risk of colon cancer through performance of physical activity. However, difficulties in estimating the exact amount of activity needed and frequency and intensity of activity result in only crude estimates of dose needed for a protective effect. Much of the literature suggest that more intense activity is needed to reduce colon cancer risk and that somewhere between 3.5 and 4 hours of vigorous activity per week may be needed to optimise protection. Several biological mechanisms have been proposed to explain the association between physical activity and colon cancer; many of these mechanisms also support the observation that intense activities are most protective. Biological mechanisms include: physical activity increasing gut motility; enhancing the immune system; decreasing insulin and insulin-like growth factor levels; decreasing obesity; enhancing free radical scavenger systems; and influencing prostaglandin levels. The evidence taken together provides strong support for lack of physical activity being causally related to colon cancer. It has been estimated that 12-14% of colon cancer could be attributed to lack of frequent involvement in vigorous physical activity.
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PMID:Physical activity and colorectal cancer. 1504 16

The discovery of insulin receptor substrate (IRS) proteins and their role to link cell surface receptors to the intracellular signaling cascades is a key step to understanding insulin and insulin-like growth factor (IGF) action. Moreover, IRS-proteins coordinate signals from the insulin and IGF receptor tyrosine kinases with those generated by proinflammatory cytokines and nutrients. The IRS2-branch of the insulin/IGF signaling cascade has an important role in both peripheral insulin response and pancreatic beta-cell growth and function. Dysregulation of IRS2 signaling in mice causes the failure of compensatory hyperinsulinemia during peripheral insulin resistance. IRS protein signaling is down regulated by serine phosphorylation or proteasome-mediated degradation, which might be an important mechanism of insulin resistance during acute injury and infection, or chronic stress associated with aging or obesity. Understanding the regulation and signaling by IRS1 and IRS2 in cell growth, metabolism and survival will reveal new strategies to prevent or cure diabetes and other metabolic diseases.
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PMID:Insulin receptor substrate proteins and diabetes. 1518 Feb 98

The association of acanthosis nigricans, skin tags, diabetes mellitus due to insulin resistance, and obesity in adolescents and young adults represents a well defined syndrome. Hyperandrogenism may also be present. The endocrine origin of this condition is beyond doubt. Insulin and insulin-like growth factor-1, and their receptors on keratinocytes are obviously involved in the complex regulations leading to the peculiar epidermal hyperplasia. This condition is unrelated to other types of acanthosis nigricans, including the congenital and the paraneoplastic types. Control of obesity contributes largely to reverse the whole process, essentially by reducing both insulin resistance and compensatory hyperinsulinemia. Several drugs including metformin, octreotide, retinoids and topical colecalciferol (vitamin D(3)) analogs are also beneficial in clearing acanthosis nigricans.
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PMID:Acanthosis nigricans associated with insulin resistance : pathophysiology and management. 1518 99

Progress in cancer prevention research is being facilitated by the use of animal models displaying specific genetic susceptibilities for cancer, such as mice deficient in one (+/-) or both (-/-) alleles of the p53 tumor suppressor gene. Our lab, which focuses on nutrition (particularly energy balance/obesity) and molecular carcinogenesis, has shown in p53-/- mice that calorie restriction (CR) increases the latency of spontaneous tumor development (mostly lymphomas) approximately 75%, decreases serum insulin-like growth factor (IGF)-1 and leptin levels, and induces apoptosis in immature (lymphoma-susceptible) thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and a one day/wk fast each significantly delay spontaneous tumor development (a mix of lymphomas, sarcomas, and epithelial tumors) and decreases serum IGF-1 and leptin levels, even when begun late in life. We are presently comparing and combining CR and exercise (treadmill and running wheel) to further elucidate the relationships between energy balance, p53, and tumorigenesis in these models. Furthermore, we have capitalized on the susceptibility of p53+/- mice to chronic, low-dose aromatic amine-induced bladder carcinogenesis to develop a model for evaluating bladder cancer prevention approaches. Using this model, we have established that IGF-1 mediates many of the anti-cancer effects of CR. We are currently conducting oligonucleotide microarray studies to further characterize diet-gene interactions underlying the anti-cancer effects of CR and to determine which of the CR-responsive genes are IGF-1 dependent.
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PMID:Diet-gene interactions in p53-deficient mice: insulin-like growth factor-1 as a mechanistic target. 1533 46

Apolipoprotein M (apoM) is a 26-kDa protein that is mainly associated with high-density lipoprotein (HDL) in human plasma, with a small proportion present in triglyceride-rich lipoproteins (TGRLP) and low-density lipoproteins (LDL). Human apoM gene is located in p21.31 on chromosome 6 (chromosome 17, in mouse). Human apoM cDNA (734 base pairs) encodes 188-amino acid residue-long protein. It belongs to lipocalin protein superfamily. Human tissue expression array study indicates that apoM is only expressed in liver and in kidney and small amounts are found in fetal liver and kidney. In situ apoM mRNA hybridization demonstrates that apoM is exclusively expressed in the hepatocytes and in the tubule epithelial cells in kidney. Expression of apoM could be regulated by platelet activating factor (PAF), transforming growth factors (TGF), insulin-like growth factor (IGF) and leptin in vivo and/or in vitro. It has been demonstrated that apoM expression is dramatically decreased in apoA-I deficient mouse. Hepatocyte nuclear factor-1alpha (HNF-1alpha) is an activator of apoM gene promoter. Deficiency of HNF-1alpha mouse shows lack of apoM expression. Mutations in HNF-1alpha (MODY3) have reduced serum apoM levels. Expression of apoM is significantly decreased in leptin deficient (ob/ob) mouse or leptin receptor deficient (db/db) mouse. ApoM concentration in plasma is positively correlated to leptin level in obese subjects. These may suggest that apoM is related to the initiation and progression of MODY3 and/or obesity.
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PMID:Apolipoprotein M. 1546 12

Secretory clusterin protein (sCLU) is a general genotoxic stress-induced, pro-survival gene product implicated in aging, obesity, heart disease, and cancer. However, the regulatory signal transduction processes that control sCLU expression remain undefined. Here, we report that induction of sCLU is delayed, peaking 72 h after low doses of ionizing radiation, and is dependent on the up-regulation of insulin-like growth factor-1 as well as phosphorylation-dependent activation of its receptor (IGF-1 and IGF-1R, respectively). Activated IGF-1R then stimulates the downstream Src-Mek-Erk signal transduction cascade to ultimately transactivate the early growth response-1 (Egr-1) transcription factor, required for sCLU expression. Thus, ionizing radiation exposure causes stress-induced activation of IGF-1R-Src-Mek-Erk-Egr-1 signaling that regulates the sCLU pro-survival cascade pathway, important for radiation resistance in cancer therapy.
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PMID:Delayed activation of insulin-like growth factor-1 receptor/Src/MAPK/Egr-1 signaling regulates clusterin expression, a pro-survival factor. 1568 20

Obesity is a frequent co-morbid condition associated with diffuse idiopathic skeletal hyperostosis (DISH). Serum growth hormone (GH), insulin-like growth factor (IGF-1) and insulin are significantly elevated in patients with DISH. In this study, we examined the relationship between body mass index (BMI) and basal serum GH, IGF-1, and insulin concentration in a group of 36 DISH patients. Basal serum insulin levels were significantly elevated (P<0.001) in DISH patients with a BMI>28 kg m(-2), classified as obese, compared with DISH patients with BMI ranging from 23 to 28 kg m(-2). In addition, BMI strongly positively correlated with serum insulin concentration in DISH patients (adjusted r2 = 0.348, P<0.001). However, BMI did not correlate with either basal serum GH (adjusted r2 = -0.013) or IGF-1 levels (adjusted r2 = -0.010) in DISH. We conclude that BMI does not seem to contribute to elevated serum GH and IGF-1 levels in symptomatic DISH.
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PMID:Body mass index and blood glucose: correlations with serum insulin, growth hormone, and insulin-like growth factor-1 levels in patients with diffuse idiopathic skeletal hyperostosis (DISH). 1570 52

Preeclampsia has been linked to increased risk for cardiovascular disease and, more recently, to reduced risk for breast cancer later in life. The altered chronic disease risk associated with prior preeclampsia may reflect underlying metabolic differences. In this case-control study, we examined the metabolic profiles of older mothers with and without a history of preeclampsia in their first pregnancies. At the time of the study, subjects were non-pregnant, non-smoking women who completed their first pregnancies at age 30 or older, were pre-menopausal, and were free of serious chronic disease. Cases were 13 women who experienced preeclampsia in their first pregnancies; controls were 13 women with uncomplicated first pregnancies, frequency matched to cases on race/ethnicity, current age, and age at delivery. A fasting blood sample was collected from each subject during the luteal phase (day 19-22) of the menstrual cycle and assayed for specific factors thought to be linked to hypertensive disease or breast cancer. Compared to women with uncomplicated pregnancies, those with a history of preeclampsia had significantly elevated levels of fasting serum triglycerides, insulin and glucose, and a higher fasting insulin resistance index, suggesting that women with prior preeclampsia were relatively insulin resistant. In addition, cases had higher levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) and a higher molar ratio of IGFBP-3 to IGF-1 than did controls. Adjustment for obesity and other potential confounders did not appreciably alter the magnitude of these associations. This preliminary study suggests that women with a history of preeclampsia have persistent metabolic abnormalities consistent with their observed excess risk for cardiovascular morbidity and mortality, and their apparent reduced risk for breast cancer later in life.
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PMID:Altered metabolic profiles among older mothers with a history of preeclampsia. 1573 70


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