Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0497406 (overweight)
 26,365 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity is a rapidly increasing health problem in all developed countries. Overweight rarely occurs in isolation but as part of a complex pattern of metabolic abnormalities ("metabolic syndrome" or "syndrome X") consisting of hyperlipidemia, hypoalphalipoproteinemia, type II diabetes and atherosclerosis. The disorder is considerably influenced by genetic, behavioural and nutritional factors. Recent data indicate that a group of closely related nuclear receptors, the peroxisome proliferator-activated receptors (PPARs), may be involved in the metabolic changes ultimately leading to obesity. This review summarises the latest developments in the PPAR field, with particular emphasis being placed on the physiological function of PPAR alpha during various nutritional states, and the possible role of PPAR alpha in obesity.
 ...
PMID:The role of PPAR alpha in obesity. 1159 Sep 95

Obesity may be a low-grade systemic inflammatory disease. Overweight and obese children and adults have elevated serum levels of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and leptin, which are known markers of inflammation and closely associated with cardiovascular risk factors and cardiovascular and non-cardiovascular causes of death. This may explain the increased risk of diabetes, heart disease, and many other chronic diseases in the obese. The complex interaction between several neurotransmitters such as dopamine, serotonin, neuropeptide Y, leptin, acetylcholine, melanin-concentrating hormone, ghrelin, nitric oxide, and cytokines and insulin and insulin receptors in the brain ultimately determines and regulates food intake. Breast-feeding of more than 12 mo is associated with decreased incidence of obesity. Breast milk is a rich source of long-chain polyunsaturated fatty acids (LCPUFAs) and brain is especially rich in these fatty acids. LCPUFAs inhibit the production of proinflammatory cytokines and enhance the number of insulin receptors in various tissues and the actions of insulin and several neurotransmitters. LCPUFAs may enhance the production of bone morphogenetic proteins, which participate in neurogenesis, so these fatty acids might play an important role in brain development and function. It is proposed that obesity is a result of inadequate breast feeding, which results in marginal deficiency of LCPUFAs during the critical stages of brain development. This results in an imbalance in the structure, function, and feedback loops among various neurotransmitters and their receptors, which ultimately leads to a decrease in the number of dopamine and insulin receptors in the brain. Hence, promoting prolonged breast feeding may decrease the prevalence of obesity. Exercise enhances parasympathetic tone, promotes antiinflammation, and augments brain acetylcholine and dopamine levels, events that suppress appetite. Acetylcholine and insulin inhibit the production of proinflammatory cytokines and provide a negative feedback loop for postprandial inhibition of food intake, in part, by regulating leptin action. Statins, peroxisome proliferator-activated receptor-gamma binding agents, non-steroidal antiinflammatory drugs, and infant formulas supplemented with LCPUFAs, and LCPUFAs themselves, which suppress inflammation, may be beneficial in obesity.
 ...
PMID:Is obesity an inflammatory condition? 1174 55

Recent research suggests that the Pro12Ala variant in peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) is associated with diabetes- and obesity-related traits, and that its effects may be modified by obesity status. We characterized this variant in a population-based sample of 1,441 middle-aged African-American individuals with respect to diabetes-, obesity-, and other cardiovascular-related traits, both cross-sectionally and prospectively. The overall frequency of Ala12 was 1.9% (95% CI 1.5-2.5%), significantly lower than in Caucasian populations. Consistent with previous findings in Caucasians, African Americans with type 2 diabetes tended to be less likely to have the Pro/Ala genotype than those without (odds ratio [OR] 0.64, 95% CI 0.34-1.20); however, this OR was not statistically significant. Among nonobese individuals, the Pro/Ala genotype was associated with significantly lower ln(insulin) (P = 0.001), lower ln(HOMA-IR) (homeostasis model assessment of insulin resistance) (P = 0.002), higher fasting glucose-to-insulin ratio (P = 0.005), and lower diastolic blood pressure (P = 0.02). Among overweight individuals (BMI 25-29.9 kg/m(2)), the Pro/Ala genotype was associated with greater BMI (P = 0.02), waist-to-hip ratio (P = 0.01), and waist circumference (P = 0.04). Among obese individuals, there was no association between any of the diabetes- or obesity-related traits and the Pro12Ala PPAR-gamma2 variant. We conclude that among nonobese African Americans, the Pro/Ala genotype is associated with markers of greater insulin sensitivity.
 ...
PMID:Pro12Ala of the peroxisome proliferator-activated receptor-gamma2 gene is associated with lower serum insulin levels in nonobese African Americans: the Atherosclerosis Risk in Communities Study. 1276 72

This study analyzes the relationship between risk factors related to overweight/obesity, insulin resistance, lipid tolerance, hypertension, endothelial function and genetic polymorphisms associated with: i) appetite regulation (leptin, melanocortin-3-receptor (MCR-3), dopamine receptor 2 (D2R)); ii) adipocyte differentiation and insulin sensitivity (peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), tumor necrosis factor-alpha (TNF-alpha)); iii) thermogenesis and free fatty acid (FFA) transport/catabolism (uncoupling protein-1 (UCP1), lipoprotein lipase (LPL), beta2- and beta3-adrenergic receptor (beta2AR, beta3AR), fatty acid transport protein-1 (FATP-1) and iv) lipoproteins (apoliprotein E (apoE), apo CIII). The 122 members of 40 obese Caucasian families from southern Poland participated in the study. The genotypes were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) or by direct sequencing. Phenotypes related to obesity (body mass index (BMI), fat/lean body mass composition, waist-to-hip ratio (WHR)), fasting lipids, glucose, leptin and insulin, as well as insulin during oral glucose tolerance test (OGTT) (4 points within 2 hours) and during oral lipid tolerance test (OLTT) (5 points within 8 hours) were assessed. The insulin sensitivity indexes: homeostasis model assessment of insulin resistance, whole body insulin sensitivity index, hepatic insulin sensitivity and early secretory response to an oral glucose load (HOMA-IR, ISI-COMP, ISI-HOMA and DELTA) were calculated. The single gene mutations such as C105 T OB and Pro115 Gln PPAR-gamma2 linked to morbid obesity were not detected in our group. A weak correlation between obesity and certain gene polymorphisms was observed. Being overweight (25 < BMI > or = 30 kg/m2) significantly correlated with worse FFA tolerance in male PPAR-gamma2 12Pro, LPL-H (G) allele carriers. Insulin resistance was found in female PPAR-gamma2 Pro12, TNF-alpha (-308A) and LPL-H (G) allele carriers. Hypertension linked to the PPAR-gamma2 Pro allele carriers was characterized by high leptin output during OLTT. We conclude that the polymorphisms we investigated were weakly correlated with obesity but significantly modified the risk factors of the metabolic syndrome.
 ...
PMID:Analysis of candidate genes in Polish families with obesity. 1520 83

Several genetic variants of peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) have been identified, among which Pro12Ala, a missense mutation in exon 2, is highly prevalent in Caucasian populations. Up to now, conflicting results with regard to the association between this mutation and complex traits, such as obesity, insulin sensitivity and Type 2 diabetes, have been reported. We investigated the influence of the Pro12Ala polymorphism of PPAR-gamma2 on insulin sensitivity in a large Italian population sample, n=1215, in whom extensive clinical and biochemical analyses were performed. To estimate the insulin sensitivity status, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated; in the obese/overweight subjects an oral glucose tolerance test (OGTT) was also performed and the Matsuda insulin sensitivity index (ISI) calculated. The insulin secretion index (homeostasis model assessment of percent beta-cell function, HOMA-beta%) was utilized to evaluate beta-cell function. The effect of the Pro12Ala polymorphism on quantitative variables was tested using multiple linear regression analysis. X12Ala (either Pro12Ala or Ala12Ala) genotype was associated with significantly lower fasting insulin levels compared to Pro/Pro (P=0.01 after correction for multiple comparisons) in all subjects. Consistent with this finding, significantly lower HOMA-IR was observed in X12Ala carriers (P=0.013 after correction for multiple comparisons) in all cohort. Moreover, no significant interaction effect was observed between body mass index and X12Ala polymorphism and between gender and X12Ala polymorphism in modulating insulin sensitivity. Our observations substantially extend previous findings and demonstrated that X12Ala variant is significantly associated with greater insulin sensitivity.
 ...
PMID:The common PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity. 1536 18

There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs--the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar). The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan--(alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of metabolic syndrome. Clinical evidences obtained from bezafibrate-based studies strongly support the concept of pan-PPAR therapeutic approach to conditions which comprise the metabolic syndrome. However, from a biochemical point of view, bezafibrate is a PPAR ligand with a relatively low potency. More powerful new compounds with pan-PPAR activity and proven long-term safety should be highly effective in a clinical setting of patients with coexisting relevant lipid and glucose metabolism disorders.
 ...
PMID:Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons. 1616 52

When preparing peroxisome proliferator-activated receptor (PPAR)alpha:low-density lipoprotein receptor (LDLR) (-/-) double knockout mice, we unexpectedly found a unique gender- and age-specific obesity in the F1 generation, PPARalpha (+/-):LDLR (+/-), even in mice fed standard chow. Body weights of the male heterozygous mice increased up to about 60 g at 75 weeks of age, then decreased by about 30 g at 100 weeks of age. More than 95% of the heterozygous mice between 35- and 75-week-olds were overweight. Of interest, the obese heterozygous mice also exhibited hyperinsulinemia correlating with moderate insulin resistance. Hepatic gene expression of LDLR was lower than expected in the heterozygous mice, particularly at 50 and 75 weeks of age. In contrast, the hepatic expression of PPARalpha was higher than expected in obese heterozygous mice, but decreased in non-obese older heterozygous mice. Modulated expression of these genes may be partially associated with the onset of the hyperinsulinemia.
 ...
PMID:Haploinsufficiency in the PPARalpha and LDL receptor genes leads to gender- and age-specific obesity and hyperinsulinemia. 1701 21

Previous studies have sought to associate the Pro12Ala variant of the peroxisome proliferator-activated receptor gamma2 (PPARG2) gene with type 2 diabetes, insulin resistance, and obesity, with controversial results. We have determined the Pro12Ala variant frequency in 370 nondiabetic Mexican Mestizo subjects and in five Mexican Amerindian groups and have investigated its possible association with lipid metabolism, insulin serum levels, and obesity in three of these populations. Two independent case-control studies were conducted in 239 nondiabetic individuals: 135 case subjects (BMI > or = 25 kg/m2) and 104 control subjects (BMI < 25 kg/m2). The PPARG2 Ala12 allele frequency was higher in most Amerindian populations (0.17 in Yaquis, 0.16 in Mazahuas, 0.16 in Mayans, and 0.20 in Triquis) than in Asians, African Americans, and Caucasians. The Pro12Ala and Ala12Ala (X12Ala) genotypes were significantly associated with greater BMI in Mexican Mestizos and in two Amerindian groups. X12Ala individuals had a higher risk of overweight or obesity than noncarriers in Mestizos (OR = 3.67; 95% CI, 1.42-9.48; p = 0.007) and in Yaquis plus Mazahuas (OR = 3.21; 95% CI, 1.27-8.11; p = 0.013). Our results provide further support of the association between the PPARG2 Ala12 allele and risk of overweight or obesity in Mestizos and two Amerindian populations from Mexico.
 ...
PMID:Association of PPARG2 Pro12Ala variant with larger body mass index in Mestizo and Amerindian populations of Mexico. 1798 60

The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor involved in lipid metabolism, adipocyte differentiation and regulation of insulin sensitivity, and is associated with Type 2 diabetes (T2DM). The association of the C1431T silent mutation and the Pro12Ala missense transversion within the PPARgamma gene with the development of T2DM or obesity has often yielded contradictory results. We examined the association of the PPARgamma Pro12Ala and C1431T gene variants and their haplotypes with the susceptibility to T2DM. This was a retrospective study involving 491 T2DM patients and 400 age- and gender-matched controls. Pro12Ala and C1431T genotyping was done by PCR-RFLP analysis. Comparable frequencies of the mutant 12Ala (0.07 vs 0.08, p=0.216) and 1431T (0.12 vs 0.10, p=0.189) alleles, and Pro12Ala (p=0.218) and C1431T (p=0.421) genotypes were seen between patients and in nondiabetic control subjects. While no difference was noted in the distribution of Pro12Ala- C1431T haplotypes and genotypes between patients and controls, the PPARgamma 12Ala, but not 1431T, allele was significantly associated with lower body mass index (BMI) (< or =25.0) among patients. Regression analysis confirmed the association of the Pro12Ala (odds ratio =5.340; 95% confidence interval =1.044-27.311) with normal (BMI<25.0) but not with overweight/obesity among T2DM patients. Despite its association with lower BMI among T2DM patients, the PPARgamma gene does not appear to markedly influence Type 2 diabetes among Tunisian subjects.
 ...
PMID:Association of the peroxisome proliferator-activated receptor-gamma2 Pro12Ala but not the C1431T gene variants with lower body mass index in Type 2 diabetes. 1825 Jun 15

Cardiovascular disease (CVD) is the leading cause of death in the United States and many parts of the world. Potentially modifiable risk factors for CVD include tobacco use, physical inactivity, hypertension, elevated low-density lipoprotein cholesterol, and a cluster of interrelated metabolic risk factors. Over the last several decades, efforts to prevent or treat CVD risk factors have resulted in significantly lower rates of CVD-related mortality. However, many patients never achieve adequate control of CVD risk factors even when these factors have been identified. In addition, the growing prevalence of obesity and type 2 diabetes mellitus (DM) threatens to undermine the improvements in CVD that have been achieved. In the United States, approximately two thirds of adults are overweight or obese, and even modest excess body weight is associated with a significantly increased risk of CVD-related mortality. Lifestyle interventions to promote weight loss reduce the risk of CVD-related illness but are difficult for patients to sustain over long periods of time. The increased incidence of obesity has also contributed to significant increases in the prevalence of other important CVD risk factors, including hypertension, dyslipidemia, insulin resistance, and type 2 DM. Pharmacologic therapies are currently available to address individual CVD risk factors, and others are being evaluated, including endocannabinoid receptor antagonists, inhibitors of peroxisome proliferator-activated receptor subtypes alpha and gamma, and several agents that modulate the activity of glucagon-like peptide-1. The new agents have the potential to significantly improve several CVD risk factors with a single medication and may provide clinicians with several new strategies to reduce the long-term risk of CVD.
 ...
PMID:Cardiovascular disease and modifiable cardiometabolic risk factors. 1845 39


1 2 3 4 Next >>