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)

Insulin-resistant states such as obesity can result in an increase in the function and mass of pancreatic beta-cells, so that insulin secretion is up-regulated and Type II diabetes does not develop. However, expansion of beta-cell mass is not indefinite and may well decrease with time. Changes in circulating concentrations of nutritional factors, such as fatty acids and/or glucose, may lead to a reduction in beta-cell mass in vivo. Few previous studies have attempted to explore the interplay between glucose, amino acids and fatty acids with respect to beta-cell mass and functional integrity. In the present study, we demonstrate that culture of clonal BRIN-BD11 cells for 24 h with the polyunsaturated fatty acid arachidonic acid (AA) increased beta-cell proliferation and enhanced alanine-stimulated insulin secretion. These effects of AA were associated with significant decreases in the cellular consumption of D-glucose and L-alanine as well as decreased rates of production of nitric oxide and ammonia. Conversely 24 h exposure to the saturated fatty acid palmitic acid (PA) was found to decrease beta-cell viability (by increasing apoptosis), increase the intracellular concentration of triacylglycerol (triglyceride), while inhibiting alanine-stimulated insulin secretion. These effects of PA were associated with significant increases in D-glucose and L-glutamine consumption as well as nitric oxide and ammonia production. However, L-alanine consumption was decreased in the presence of PA. The effects of AA, but not PA, were additionally dependent on glucose concentration. These studies indicate that AA may have a critical role in maintaining the appropriate mass and function of islet beta-cells by influencing rates of cell proliferation and insulin secretion. This regulatory effect may be compromised by high circulating levels of glucose and/or PA, both of which are elevated in Type II diabetes and may impact upon dysfunctional and apoptotic intracellular events in the beta-cell.
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PMID:Arachidonic acid, palmitic acid and glucose are important for the modulation of clonal pancreatic beta-cell insulin secretion, growth and functional integrity. 1456 Dec 12

Obesity affects about 44% of women with polycystic ovary syndrome (PCOS). Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is one of the genes involved in the differentiation of adipose tissue. In an attempt to shed light on the high percentage of obesity in PCOS, we examined polymorphisms at exons 6 and 2 of the PPAR-gamma gene in 100 PCOS patients and in 100 healthy controls matched for age and body mass index (BMI). The T allele frequency of exon 6 was significantly higher (P < 0.05) in PCOS patients compared with control women. In addition, the BMI and leptin levels were significantly higher (P < 0.05) in PCOS patients carrying the C-->T substitution than in controls. There was no significant difference in leptin levels after normalization for BMI. The Pro(12)Ala polymorphism at exon 2 was unrelated to BMI and/or leptin levels in PCOS women. In conclusion, the higher frequency of the C-->T substitution in exon 6 of the PPAR-gamma gene in PCOS women suggests that it plays a role in the complex pathogenetic mechanism of obesity in PCOS, whereas the Pro(12)Ala polymorphism does not seem to affect BMI in PCOS women.
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PMID:Exon 6 and 2 peroxisome proliferator-activated receptor-gamma polymorphisms in polycystic ovary syndrome. 1467 Nov 86

Circulating levels of the cytokine interleukin 6 (IL-6) are elevated in obesity, correlate with body mass index (BMI), and predict the development of type 2 diabetes mellitus (T2DM). A promoter polymorphism in the IL6 gene is associated with obesity, altered levels of insulin sensitivity, and T2DM. IL-6 exerts its effects by binding to the IL-6 receptor (IL-6R) and levels of IL-6R have been correlated with BMI. It is possible that IL6R variants may also be related to obesity, but to our knowledge, no study has yet examined this relationship. The objective of this study was to examine the relationship between genetic variants in the IL6R gene and obesity in Pima Indians, a population prone to excess adiposity. We sequenced 6kb of the IL6R gene, corresponding to all exons, exon-intron boundaries, and 2kb of promoter in 30 Pima Indians. We identified six single nucleotide polymorphisms (SNPs) in the IL6R gene: a predicted Asp --> Ala substitution at position 358, a variant in the 3'-untranslated region, and 4 intronic SNPs. All SNPs were in strong linkage disequilibrium (D' >/= 0.90) and varied in minor allele frequency from 0.33 to 0.48. Association between IL6R genotype and BMI (kg/m(2)) was assessed in approximately 700 nondiabetic, full-heritage Pima Indians. For each SNP, individuals carrying the variant allele had a higher mean BMI compared to those with the wild-type allele (range: [37.3+/-7.2-38.2+/-7.0] vs. [35.5+/-7.3-36.0+/-7.5]; P=0.02-0.004). Our findings suggest that genetic variants in the IL6R gene may play a role in susceptibility to obesity. Assessment of these SNPs in other populations will be useful to determine the magnitude of obesity risk.
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PMID:Variants in the interleukin 6 receptor gene are associated with obesity in Pima Indians. 1468 Sep 81

The importance of the genetic component on adipose tissue accumulation has been clearly demonstrated. Among the candidate genes investigated, there are those that regulate thermogenesis and, thus, can affect energy expenditure. The uncoupling proteins (UCPs) are a family of proteins that uncouple respiration leading to generation of heat and increased energy expenditure. Contradictory data indicate that allelic variants in their coding genes might be associated with obesity. In this study we evaluated the role of two allelic variants of the UCP2 gene in obesity and the association with its sub-phenotypic characteristics. To this aim, 360 morbidly obese patients [age: 45 +/- 15 yr, body mass index (BMI): 46 +/- 7 kg/m2] and 103 normal weight subjects (BMI < 24 kg/m2) were genotyped for the 45 bais-pair (bp) insertion/deletion (I/D) in the 3'-untraslated region of exon 8 of the UCP2 gene while the presence of an Ala/Val substitution at codon 55 (Ala55Val) of the same gene was studied in 104 obese and 50 lean subjects. Patients also underwent a study protocol including measurements of BMI, waist-to-hip ratio (WHR), resting energy expenditure (REE), energy intake, fat mass (FM) and free fat mass (FFM), total cholesterol (TCH), high density lipoprotein (HDL) cholesterol, triacylglyceroles (TG), leptin levels, basal glucose, immunoreactive insulin (IRI), glycated haemoglobin (HbA1c), insulin sensitivity and thyroid hormones. No significant association between the two polymorphisms studied and the clinical, metabolic and anthropometric parameters characteristic of the obese phenotype was found. These results, in accordance with similar findings previously obtained in other ethnic groups, suggest that these two UCP2 allelic variants may not have a direct role in the pathogenesis and development of obesity.
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PMID:Lack of association between UCP2 gene polymorphisms and obesity phenotype in Italian Caucasians. 1475 71

Apolipoprotein B (apoB) is the major proteic component of LDL, VLDL and chylomicrons. Numerous polymorphisms of the apolipoprotein B gene have been described. Particularly, a polymorphism of insertion/deletion located in the coding part of the signal peptide of apoB, associated with modifications of lipid concentrations and the risk of cardiovascular disease, has been reported in the general population. Since obesity is frequently associated with dyslipidemias, the aim of our study was to assess the effect of the insertion/deletion polymorphism of the apolipoprotein B gene on lipid levels in obese subjects. 234 unrelated caucasian obese subjects (74 men and 160 women, aged 39.3 +/- 10.5, BMI : 32.8 +/- 4.7) were recruited. The insertion/deletion polymorphism was determined by electrophoresis in polyacrylamide gels after PCR amplification. The relative frequencies of the Ins and Del alleles were 0.71 and 0.29 respectively. These frequencies were similar to those found in other Caucasian populations. In the whole population, individuals with the Del/Del genotype had significantly higher total-cholesterol to HDL-cholesterol ratios (p = 0.004), LDL-cholesterol to HDL-cholesterol ratios (p = 0.01) and TG-VLDL levels (p < 0.05). They also showed a tendency for higher triglyceride levels (p = 0.09) and lower HDL-cholesterol, apolipoprotein AI and LpAI levels. The allele deletion results in the absence of three amino acids (Leu-Ala-Leu) in the signal peptide of apo B. In the obese people, these structural changes may have some effect on lipid metabolism and cause variation in serum lipid concentrations.
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PMID:[Polymorphism insertion/deletion of apolipoprotein B gene: effect on lipid levels in obese patients]. 1504 70

Agouti-related protein (AGRP) is one of only two naturally known antagonists of G-protein-coupled receptors (GPCRs) identified to date. Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these melanocortin receptors. Insight into putative interactions between the antagonist AGRP amino acids with the melanocortin-4 receptor (MC4R) may be important for the design of unique ligands for the treatment of obesity related diseases and is currently lacking in the literature. A three-dimensional homology molecular model of the mouse MC4 receptor complex with the hAGRP(87-132) ligand docked into the receptor has been developed to identify putative antagonist ligand-receptor interactions. Key putative AGRP-MC4R interactions include the Arg111 of hAGRP(87-132) interacting in a negatively charged pocket located in a cavity formed by transmembrane spanning (TM) helices 1, 2, 3, and 7, capped by the acidic first extracellular loop (EL1) and specifically with the conserved melanocortin receptor residues mMC4R Glu92 (TM2), mMC4R Asp114 (TM3), and mMC4R Asp118 (TM3). Additionally, Phe112 and Phe113 of hAGRP(87-132) putatively interact with an aromatic hydrophobic pocket formed by the mMC4 receptor residues Phe176 (TM4), Phe193 (TM5), Phe253 (TM6), and Phe254 (TM6). To validate the AGRP-mMC4R model complex presented herein from a ligand perspective, we generated nine chimeric peptide ligands based on a modified antagonist template of the hAGRP(109-118) (Tyr-c[Asp-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH(2)). In these chimeric ligands, the antagonist AGRP Arg-Phe-Phe residues were replaced by the melanocortin agonist His/D-Phe-Arg-Trp amino acids. These peptides resulted in agonist activity at the mouse melanocortin receptors (mMC1R and mMC3-5Rs). The most notable results include the identification of a novel subnanomolar melanocortin peptide template Tyr-c[Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) that is equipotent to alpha-MSH at the mMC1, mMC3, and mMC5 receptors but is 30-fold more potent than alpha-MSH at the mMC4R. Additionally, these studies identified a new and novel >200-fold MC4R versus MC3R selective peptide Tyr-c[Asp-D-Phe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) template. Furthermore, when the His-DPhe-Arg-Trp sequence is used to replace the hAGRP Arg-Phe-Phe residues in the "mini"-AGRP (hAGRP87-120, C105A) template, a potent nanomolar agonist resulted at the mMC1R and MC3-5Rs.
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PMID:Identification of putative agouti-related protein(87-132)-melanocortin-4 receptor interactions by homology molecular modeling and validation using chimeric peptide ligands. 1508 18

Obesity and stress inhibit insulin action by activating protein kinases that enhance serine phosphorylation of IRS1 and have been thus associated to insulin resistance and the development of type II diabetes. The protein kinase C (PKC) is activated by free-fatty acids, and its activity is higher in muscle from obese diabetic patients. However, a molecular link between PKC and insulin resistance has not been defined yet. Here we show that PKC phosphorylates IRS1 at serine 1101 blocking IRS1 tyrosine phosphorylation and downstream activation of the Akt pathway. Mutation of Ser(1101) to alanine makes IRS1 insensitive to the effect of PKC and restores insulin signaling in culture cells. These results provide a novel mechanism linking the activation of PKC to the inhibition of insulin signaling.
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PMID:Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). 1536 19

Obesity is a prominent feature of the Bardet-Biedl syndrome (BBS), one subset of which, BBS6, is due to mutations in the chaperonin-like gene termed the McKusick-Kaufman syndrome (MKKS) gene. We tested whether variation in MKKS contributes to common and probably polygenic forms of obesity by performing mutation analysis of the coding region in 60 Danish white men with juvenile-onset obesity. Five variants were identified, including two synonymous mutations (Pro(39)Pro and Ile(178)Ile) and three nonsynonymous variants (Ala(242)Ser, Arg(517)Cys, and Gly(532)Val). Furthermore, the rare Ala(242)Ser was identified in two families and showed partial cosegregation with obesity. The Pro(39)Pro, Ile(178)Ile, and Arg(517)Cys variants are in complete linkage disequilibrium and defined a prevalent haplotype. In a case-control study, the Arg(517)Cys polymorphism allele prevalence was 11.4% [95% confidence interval (CI), 9.7-13.0] among 744 men with juvenile-onset obesity and 9.3% (CI, 7.9-10.7) among 867 control subjects (P = 0.048). However, among middle-aged men the allelic prevalence was 9.7% (CI, 7.9-11.4) among 523 obese men and 12.2% (CI, 10.8-13.6) among 1051 lean men (P = 0.037). In conclusion, it is unlikely that MKKS variants play a major role in the pathogenesis of nonsyndromic obesity, although in rare cases the A242S allele may contribute to obesity.
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PMID:Variation of the McKusick-Kaufman gene and studies of relationships with common forms of obesity. 1548 80

Increased circulating levels of liver enzymes emerging during treatment with psychotropic drugs are frequently encountered and, in general, attributed to drug metabolism or toxic effects. Because obesity was shown to be associated with elevated liver enzyme levels in different non-psychiatric study samples, we hypothesized that drug-induced weight gain might be an additional causative factor. We tested this hypothesis in 67 inpatients who received psychopharmacological treatment across five weeks. Stepwise linear regression was used to predict changes in the serum levels of aspartate-amino transferase (ASAT) and alanine-amino transferase (ALAT) by changes in the body mass index (BMI), by changes in other biological parameters related to body weight (tumor necrosis factor-alpha [TNF-alpha], soluble TNF receptors [sTNF-R], interleukin-6 [IL-6], leptin plasma levels) and by the respective liver enzyme baseline level. BMI changes from baseline to endpoint were significantly associated with the changes in ALAT and ASAT levels across five weeks of treatment and with ALAT and ASAT levels at the end point of the study. The baseline levels of ALAT and ASAT also had a significant impact on these liver enzyme level changes, whereas all other variables had not. These results suggest that weight gain-associated metabolic changes occurring during treatment with psychotropic drugs have consistent and clinically relevant effects on the liver.
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PMID:Elevation of liver enzyme levels during psychopharmacological treatment is associated with weight gain. 1550 22

Several genetic variants of peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a molecule known to be involved in transcription of target genes, have been identified. Pro12Ala, a missense mutation in exon 2 of the gene, is highly prevalent in Caucasian populations. Conflicting conclusions about the association between this mutation and complex traits such as obesity, insulin sensitivity, and T2DM have been reported. We have investigated the association of PPAR-gamma2 Pro12Ala polymorphism with measures of insulin sensitivity in a population of Italian obese children (n = 200; mean age, 10.38 +/- 2.8 y) in whom clinical and biochemical analyses were performed. To estimate the insulin sensitivity status, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated in all subjects. The effect of the Pro12Ala polymorphism on quantitative variables was tested using multiple linear regression analysis. The frequency of Ala carriers was 17%, similar to that reported in other adult Caucasian populations. The X12Ala (either Pro12Ala or Ala12Ala) genotype was associated with significantly lower fasting insulin levels compared with Pro/Pro (p = 0.008). Consistent with this finding, significantly lower HOMA-IR was observed in X12Ala carriers (p = 0.023). In conclusion, our observations demonstrate that the X12Ala variant is significantly associated with greater insulin sensitivity in childhood obesity. Because obesity is one of the most important risk factors for cardiovascular diseases and type 2 diabetes, obese children, who are presumably at a higher risk, may be protected from these diseases by the phenotypic effect of the Ala 12 allele on insulin resistance.
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PMID:PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity in childhood obesity. 1553 38


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