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)

The beta-adrenergic system is involved in the control of energy metabolism and expenditure. The beta2-adrenergic receptor (beta2-AR) gene shows polymorphisms that have been associated with obesity in several studies. In vitro and in vivo studies suggest differences in beta2-AR-mediated function between these polymorphisms. The aim of this study was to investigate the influence of genetic variation in codon 16 of the beta2-AR gene on energy metabolism in humans. Thirty-four subjects were recruited [Gly16Gly (n = 13), Gly16Arg (n = 16), or Arg16Arg (n = 5)]. The beta2-AR was stimulated with two doses of salbutamol (50 and 100 ng/kg fat-free mass per minute) after blockade of the beta1-adrenergic receptors with atenolol. Energy expenditure and plasma substrate and hormone concentrations were measured. The increase in energy expenditure (DeltaEE) was significantly different among groups in which the Arg16Arg group showed the lowest increase (P < 0.05 vs. Gly carriers). In a multiple regression model, variations in the increase in nonesterified fatty acid concentration during salbutamol infusion (partial r = 0.51) and the polymorphism contributed significantly to the variation in DeltaEE. Thirty-five percent of the variation in DeltaEE was explained by these two factors. We conclude that subjects with the Arg16Arg polymorphism of the beta2-AR gene have a reduced thermogenic response to beta2-adrenergic stimulation. Although this relatively small study needs confirmation, the findings support a role for this polymorphism in the development and maintenance of overweight and obesity.
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PMID:beta2-adrenergic receptor polymorphisms and salbutamol-stimulated energy expenditure. 1568 40

The nucleus tractus solitarius (NTS) receives dense terminations from cranial visceral afferents, including those from the gastrointestinal (GI) system. Although the NTS integrates peripheral satiety signals and relays this signal to central feeding centers, little is known about which NTS neurons are involved or what mechanisms are responsible. Proopiomelanocortin (POMC) neurons are good candidates for GI integration, because disruption of the POMC gene leads to severe obesity and hyperphagia. Here, we used POMC-enhanced green fluorescent protein (EGFP) transgenic mice to identify NTS POMC neurons. Intraperitoneal administration of cholecystokinin (CCK) induced c-fos gene expression in NTS POMC-EGFP neurons, suggesting that they are activated by afferents stimulated by the satiety hormone. We tested the synaptic relationship of these neurons to visceral afferents and their modulation by CCK and opioids using patch recordings in horizontal brain slices. Electrical activation of the solitary tract (ST) evoked EPSCs in NTS POMC-EGFP neurons. The invariant latencies, low failure rates, and substantial paired-pulse depression of the ST-evoked EPSCs indicate that NTS POMC-EGFP neurons are second-order neurons directly contacted by afferent terminals. The EPSCs were blocked by the glutamate antagonist 2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline. CCK increased the amplitude of the ST-stimulated EPSCs and the frequency of miniature EPSCs, effects attenuated by the CCK1 receptor antagonist lorglumide. In contrast, the orexigenic opioid agonists [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin and met-enkephalin inhibited both ST-stimulated EPSCs and the frequency of miniature EPSCs. These findings identify a potential satiety pathway in which visceral afferents directly activate NTS POMC-EGFP neurons with excitatory inputs that are appropriately modulated by appetite regulators.
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PMID:Proopiomelanocortin neurons in nucleus tractus solitarius are activated by visceral afferents: regulation by cholecystokinin and opioids. 1581 88

We assessed interactions between polymorphisms in the beta-adrenergic receptor genes and longitudinal changes in obesity from childhood to adulthood using longitudinal data collected over a 24-year period from 1973 to 1996. Sex- and age-stratified analyses using random coefficients models were used to examine gene-gene interaction effects on obesity measures in 1179 African-American and white men and women (71% white, 57% women). Suggestive evidence for an interaction (p = 0.022) between the beta1- and beta2-adrenergic receptors was observed in men for longitudinal change in BMI. Men with Gly/Gly genotypes for both the beta1 and beta2 receptors showed significant increases (approximately 0.6%/yr) in BMI from childhood to adulthood. Women showed suggestive evidence for an interaction (p = 0.035) between the beta1- and beta3-adrenergic receptors for change over time in BMI. Women with Gly/Gly genotypes at the beta1-receptor and carrying at least one beta3-Arg allele showed notable increases in BMI. The regulation of lipolysis and development of obesity differ markedly between men and women and may be influenced by genetic polymorphisms, which contribute to the efficiency of the beta-adrenergic receptors, and hormonal effects on adrenergic receptor activity.
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PMID:Interactive effects between polymorphisms in the beta-adrenergic receptors and longitudinal changes in obesity. 1583 37

Adrenergic receptors regulate lipid mobilization, energy expenditure and glycogen breakdown. The beta(2) adrenergic receptor (beta(2)-AR) gene may constitute a potential candidate gene to explain part of the genetic predisposition to human obesity and correlated traits. With regard to the association between beta(2)-AR gene polymorphisms and obesity-related metabolic disorders, published reports give conflicting results. We investigated the role of three polymorphisms, and related haplotypes of the beta(2)-AR in the obesity and related traits in a cohort of overweight/obese subjects. We characterized one single nucleotide polymorphism (SNP) in the promoter region (5'LC-Cys19Arg) and two in the coding region (Gly16Arg and Gln27Glu) of the beta(2)-AR in 642 consecutively recruited overweight/obese subjects in whom extensive clinical and biochemical analysis was performed. The effect of the polymorphisms on quantitative variables was investigated using multiple linear regression analysis. 5'LC-Cys19 homozygous showed higher triglyceride and LDL-cholesterol levels compared to 5'LC-Arg19 homozygous (P=0.03 and P=0.01, respectively). Similar increase in triglyceride and LDL-cholesterol levels was observed for Arg/Arg genotype compared to Gly/Gly genotype of Gly16Arg polymorphism (P=0.02 and P=0.01, respectively) and for Gln/Gln genotype compared to Glu/Glu genotype of the Gln27Glu polymorphism (P=0.01 and P=0.03, respectively). The 5'LC-Cys(19)Arg(16)Gln(27) haplotype determined a significant increase in triglyceride and LDL-cholesterol levels compared to 5'LC-Arg(19)Gly(16)Glu(27) haplotype (P=0.05 and P=0.02, respectively). Our findings provide additional weight to previous observations on the influence of these three genetic variants on lipid phenotypes; particularly on the increase of triglycerides and LDL-cholesterol levels in overweight/obese subjects carrying the 5'LC-Cys(19)Arg(16)Gln(27) haplotype.
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PMID:Association of beta2 adrenergic receptor polymorphisms and related haplotypes with triglyceride and LDL-cholesterol levels. 1625 89

Both obesity and increased endorphin production are associated with an increase in blood pressure. We have previously demonstrated that the acute and chronic central nervous system (CNS) administration of beta-endorphin can increase or decrease blood pressure, respectively. Also high fat (HF) diet-induced obesity is associated with increased hypothalamic mu opioid receptors and increased blood pressure in response to ss-endorphins. In this study we investigated the effect of high fat diet-induced obesity on blood pressure, heart rate, and physical activity as well as determined the effect of mu opioids in unanesthetized rats. Male Wistar rats were implanted with a radiotelemetry transmitter to record cardiovascular dynamics and activity. They were fed either a HF diet (HF; 59% fat by caloric content, soy bean oil) or regular chow (control; 12% fat by caloric content). HF rats had higher body weights and their total caloric intake was greater than controls. The systolic blood pressures (SBP) were greater in the HF-obese rats. After 12-13 weeks the rats were infused chronically with a mu opioid agonist (D)-Ala(2), N-Me-Phe(4), Gly(5)-ol]-ENKEPHALIN (DAMGO) or a mu opioid antagonist ss-funaltrexamine (beta-FNA) via intracerebroventricular cannula. DAMGO increased the SBP and heart rate in controls, but not in HF obese rats. DAMGO did not affect physical activity; beta-FNA decreased SBP and increased HR in controls. We concluded that HF rats consumed more calories, gained more weight, and had higher SBP. However, the responsiveness to the mu-receptor agonist was not higher in the HF rats.
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PMID:The effect of high fat-induced obesity on cardiovascular and physical activity and opioid responsiveness in conscious rats. 1654 39

Genes involved in the regulation of catecholamine function may be important in obesity because of the role catecholamines play in energy expenditure and lipolysis. To determine if common single nucleotide polymorphisms (SNPs) in beta(1)-adrenergic receptor (ADRB1), beta(2)-adrenergic receptor (ADRB2), beta(3)-adrenergic receptor (ADRB3), and alpha(2)-adrenergic receptor (ADRA2A) genes associate with obesity and metabolic alterations, we recruited 74 healthy African American and 161 white men and women (age, 18-49 years) to participate in this case-control genetic association study. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism. Associations between genotype and body mass index (BMI), percentage of body fat (by measuring skinfold thickness in 7 different sites), fasting (12-hour) plasma glucose, insulin, potassium concentrations, glycated hemoglobin, and insulin resistance (homeostasis model assessment [HOMA(IR)] score) were performed. Among whites, the ADRB1 Arg389-->Gly variant associated with insulin concentrations and HOMA(IR): mean +/- SD values for insulin and HOMA(IR) in Arg389 homozygotes and carriers of the Gly were 10 +/- 7.0 and 12 +/- 9.4 micro IU/mL (P = .02) and 2.1 +/- 1.7 and 2.6 +/- 2.2 (P = .057), respectively. Systolic blood pressure was higher in whites for carriers of the ADBR1 Ser49 compared to Gly49 homozygotes (124 +/- 12.6 vs 119 +/- 11.3 mm Hg, respectively; P = .02). Subsequent analysis revealed that these associations were attributable to a higher BMI among obese participants. The ADRA2A G1780A SNP associated with BMI and percentage of body fat in African Americans (P = .05). Interactions were detected between ADRA2A C-1291G and ADRB2 Gln27-->Glu variants for obesity in African Americans and between ADRA2A C-1291G SNP and ADBR1 haplotype for obesity in whites. We conclude that common SNPs in adrenergic receptor genes may be important susceptibility loci for obesity and related alterations. Because of the limited size of our populations, our results should be interpreted with caution and should be replicated in larger populations.
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PMID:Association analyses of adrenergic receptor polymorphisms with obesity and metabolic alterations. 1751 7

Since the isolation and sequencing of cholecystokinin (CCK), considerable advances have been made in understanding the roles played by this peptide as a hormone and as a neuropeptide. CCK-1(A) and 2(B) receptor (R) cDNAs have been cloned; shortly thereafter, the naturally occurring CCK-1R gene-deficient rat (the Otsuka Long-Evans Tokushima Fatty (OLETF) rat) was discovered. This strain develops adult-onset diabetes with obesity, and has a 6847 base-pair deletion of the CCK-1R gene in which the promoter lesion and the first two exons are missing. At the same time, the genomic structures of CCK-1R in rats, mice, and humans were clarified. The CCK-1R gene consists of five exons interrupted by four introns. It has been determined that there is species- and tissue-specific CCK receptor heterogeneity of expression; in particular, there is evidence that the human pancreas does not express CCK-1R, while the pancreas in rodents primarily expresses CCK-1R. Although CCK-1R polymorphisms with amino acid changes such as 21Gly to Arg, 71 Arg to Gly, and 364 Val to Ile were discovered in subjects with obesity and diabetes mellitus, these changes occur sporadically. We identified two sequence changes, a G to T change in nucleotide -128, and an A to G change in nucleotide -81, in the promoter region of the CCK-1R gene. This polymorphism is considered to be a single nucleotide polymorphism (SNP) related to weight control difficulties in obese subjects as well as to psychiatric disorders. The precise molecular mechanisms of this polymorphism remain to be clarified.
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PMID:Cholecystokinin 1A receptor polymorphisms. 1758 42

The H+-coupled peptide cotransporter 1 (PepT1) mediates absorption of peptides and peptidomimetic drugs. Acute luminal leptin was reported to induce translocation of PepT1 to the enterocyte membrane in vitro and in vivo in the rat, resulting in enhanced peptide and peptidomimetic drug absorption. In this study, we analyzed chronic effects of leptin and leptin deficiency on PepT1 activity and expression in the small intestine. Wistar rats and ob/ob mice were used. Activity of PepT1 was determined by monitoring [3H]glycyl-sarcosine (Gly-Sar) transport using the jejunal loop method. The levels of PepT1 mRNA and protein were quantified by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis, respectively. Induction of chronic hyperleptinemia in rats (1 microg/g/day for 7 days; subcutaneous continuous infusion), caused a significant 25% increase (P < 0.05 versus control) in Gly-Sar transport and uptake. This effect was associated with a significant 2-fold increase in the abundance of PepT1 protein and a 6-fold increase in the levels of PepT1 mRNA. In the leptin-deficient ob/ob mice, PepT1 activity and expression were significantly reduced, and replacement of leptin (10 microg/day for 7 days; subcutaneous continuous infusion) completely restored full PepT1 expression and activity. Moreover, we showed that a 7-day challenge of the Caco-2 cells with 0.2 nM leptin induced a significant increase in PepT1 activity and protein expression, arguing for a direct action. These data demonstrate, for the first time, an impaired activity/expression of PepT1 in leptin-deficient ob/ob mice that could be restored by leptin replacement. These findings may have relevance in modulation of dietary nitrogen supply and PepT1 substrate bioavailability in obesity.
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PMID:Long-term effect of leptin on H+-coupled peptide cotransporter 1 activity and expression in vivo: evidence in leptin-deficient mice. 1762 73

The effect of anthocyanins extracted from black soybean (Glycine max L.) seed coats on body weight, adipose tissue weight, and serum lipids was evaluated in rats fed a high fat diet (HFD). Rats were raised on a normal diet (ND) (based on the AIN-93M diet), HFD (ND supplemented with 16% lard oil), HFD containing 10% black soybean, and HFD containing 0.037% black soybean anthocyanins (equivalent to that in the 10% black soybean diet). Weight gain was significantly lowered in the rats fed HFD plus black soybean anthocyanins compared with the rats fed HFD alone (P < .05) and reversed to the level of the rats fed ND. The black soybean diet also decreased body weight gain compared with the HFD (P < .05). The black soybean anthocyanins-added diet suppressed the HFD-induced weight gain in liver intermediately and tended to decrease the weights of epididymal and perirenal fat pads. The black soybean anthocyanins were also effective in improving the lipid profile. They significantly reduced the levels of serum triglyceride and cholesterol (P < .05), while they markedly increased the high-density lipoprotein-cholesterol concentration, which was decreased in the rats fed HFD (P < .05). These results indicate that the anthocyanins in black soybean seed coats have an anti-obesity effect, which can reverse the effects of HFD on body weight, adipose tissue weight, and serum lipid contents.
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PMID:Anti-obesity and hypolipidemic effects of black soybean anthocyanins. 1788 51

Adrenomedullin (AM) is a cardiovascular protective peptide produced in various organs and tissues including adipose tissue. In the present study, we measured the plasma AM levels of subjects with or without obesity by two assay methods to separately evaluate the biologically active AM-NH(2) and the intermediate form of AM-glycine (AM-Gly). We measured the total AM and AM-NH(2) levels of plasma in 52 obese and 172 non-obese residents of a Japanese community, who received regular health check-ups and had no overt cardiovascular disease. AM-Gly values were obtained by subtracting AM-NH(2) levels from those of total AM. Both the AM-NH(2) and AM-Gly levels of the subjects with obesity were higher than those without obesity, and significant relationships were noted between body mass index (BMI) and the plasma levels of the two molecular forms of AM in a simple regression analysis. Moreover, the significant factors identified by multivariate analyses were BMI and serum triglyceride for AM-NH(2) and diastolic blood pressure, insulin, high-density lipoprotein-cholesterol, and plasma renin activity for AM-Gly. These results suggest active roles for the two molecular forms of AM in metabolic disorders associated with obesity in subjects without overt cardiovascular disease.
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PMID:Increased plasma levels of the mature and intermediate forms of adrenomedullin in obesity. 1970 11


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