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)

Five mitochondrial uncoupling proteins exist in the human gemone: UCP2, expressed ubiquitously; UCP1, exclusively in brown adipose tissue (BAT); UCP3, predominantly in muscle; UCP4 and BMCP (UCP5), in brain. UCP4 is the ancestral prototype from which the other UCPn diverged. Findings on the level of organism and reconstituted recombinant proteins demonstrated that UCPn exhibit a protonophoric function, documented by overexpression in mice, L6 myotubes, INS1 cells, muscle, and yeast. In a few cases (yeast), this protonophoric function was correlated with elevated fatty acid (FA) levels. Reconstituted UCPn exhibited nucleotide-sensitive FA induced H(+) uniport. Two mechanisms, local buffering or FA cycling were suggested as an explanation. A basic UCPn role with mild uncoupling is to accelerate metabolism and reduce reactive oxygen species. UCP2 (UCP3) roles were inferred from transcriptional up-regulation mediated by FAs via peroxisome proliferator-activated receptors, cytokines, leptin signalling via hypothalamic pathway, and by thyroide and beta2 adrenergic stimulation. The latter indicated a role in catecholamine-induced thermogenesis in skeletal muscle. UCP2 (UCP3) may contribute to body weight regulation, although obesity was not induced in knockout (KO) mice. An obesity reduction in middle-aged humans was associated with the less common allele of -866 G/A polymorphism in the ucp2 gene promoter enhancing the exon 8 insertion: deletion transcript ratio. Up-regulated UCP2 transcription by pyrogenic cytokines (tumour necrosis factor alpha (TNFalpha)) suggested a role in fever. UCP2 could induce type 2 diabetes as developed from obesity due to up-regulated UCP2 transcription by FAs in pancreatic beta-cells. UCPn might be pro-apoptotic as well as anti-apoptotic, depending on transcriptional and biochemical regulation.
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PMID:Possible physiological roles of mitochondrial uncoupling proteins--UCPn. 1212 70

The effect of cold exposure, being overweight and their interaction was investigated on the response of uncoupling proteins UCP1, UCP2 and UCP3 and the alpha(2)/beta(3) adrenergic receptor (AR) balance in brown adipose tissue (BAT), as well as the involvement of leptin gene expression in white adipose tissues, in control and overweight male rats of the dietary obesity model known as the post-cafeteria model. UCP1, UCP2 and UCP3 mRNAs were up-regulated by cold, with a synergic effect of cold exposure and being overweight on UCP1 mRNA levels (with the related UCP1 protein response), and with UCP2 mRNA showing a parallel response. Furthermore, the BAT alpha(2)/beta(3) AR ratio was diminished in overweight rats. The results suggest that the UCP1-dependent thermogenic capacity in BAT of post-cafeteria overweight rats has a more sensitive response to cold exposure and that UCP2 and UCP3 could be somehow involved in the thermogenic response but differentially regulated. Moreover, the diminished alpha(2)/beta(3) AR ratio in BAT could be one of the factors involved in the more sensitive response of overweight rats to cold in terms of BAT thermogenesis-related parameters.
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PMID:Synergic effect of overweight and cold on uncoupling proteins expression, a role of alpha(2)/beta(3) adrenergic receptor balance? 1213 67

We examined the long-term effects of dietary diacylglycerol (DG) and triacylglycerol (TG) with similar fatty acid compositions on the development of obesity in C57BL/6J mice. We also analyzed the expression of genes involved in lipid metabolism at an early stage of obesity development in these mice. Compared with mice fed the high-TG diet, mice fed the high-DG diet accumulated significantly less body fat during the 8-month study period. Within the first 10 days, dietary DG stimulated beta-oxidation and lipid metabolism-related gene expression, including acyl-CoA oxidase, medium-chain acyl-CoA dehydrogenase, and uncoupling protein-2 in the small intestine but not in the liver, skeletal muscle, or brown adipose tissue, suggesting the predominant contribution of intestinal lipid metabolism to the effects of DG. Furthermore, analysis of digestion products of [(14)C]DG and those of [(14)C]TG revealed that the radioactivity levels detected in fatty acid, 1-monoacylglycerol, and 1,3-DG in intestinal mucosa were significantly higher after intrajejunal injection of DG rather than TG. Thus, dietary DG reduces body weight gain that accompanies the stimulation of intestinal lipid metabolism, and these effects may be related to the characteristic metabolism of DG in the small intestine.
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PMID:Anti-obesity effect of dietary diacylglycerol in C57BL/6J mice: dietary diacylglycerol stimulates intestinal lipid metabolism. 1217 75

The uncoupling protein (UCP) 2 gene is expressed in adipose tissues and skeletal muscles, which are important sites for variations in energy expenditure. The objective of the current study was to examine the potential impact of a C-->T substitution in exon 4, resulting in an alanine to valine substitution at codon 55, on the Metabolic Syndrome in 284 unrelated Swedish men born in 1944. The subjects were genotyped using PCR amplification of the exon 4 region of the UCP2 gene followed by digestion with the restriction enzyme EclHK1. The allelic frequencies were 0.56 for allele Ala and 0.44 for allele Val. No association was found between the Ala55Val SNP and obesity and blood levels of insulin, glucose, and lipids as well as blood pressure and circulating hormones. From these data, we conclude that the C-->T substitution in exon 4 of the UCP2 gene does not contribute to the predisposition to be affected by the Metabolic Syndrome.
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PMID:Lack of association between the uncoupling protein-2 Ala55Val gene polymorphism and phenotypic features of the Metabolic Syndrome. 1238 72

Obesity is frequently associated with type 2 diabetes. We previously observed an association of a functional G/A polymorphism in the uncoupling protein 2 (UCP2) promoter with obesity. The wild-type G allele was associated with reduced adipose tissue mRNA expression in vivo, reduced transcriptional activity in vitro, and increased risk of obesity. On the other hand, studies in animal and cell culture models identified pancreatic beta-cell UCP2 expression as a main determinant of the insulin secretory response to glucose. We therefore ascertained associations of the -866G/A polymorphism with beta-cell function and diabetes risk in obesity. We show here that the pancreatic transcription factor PAX6 preferentially binds to and more effectively trans activates the variant than the wild-type UCP2 promoter allele in the beta-cell line INS1-E. By studying 39 obese nondiabetic humans, we observed genotype differences in beta-cell function; wild-type subjects displayed a greater disposition index (the product of insulin sensitivity and acute insulin response to glucose) than subjects with the variant allele (P < 0.03). By comparing obese subjects with and without type 2 diabetes, we observed genotype-associated differences in diabetes prevalence that translated into a twofold age-adjusted risk reduction in wild-type subjects. Thus, the more common UCP2 promoter G allele, while being conducive for obesity, affords relative protection against type 2 diabetes.
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PMID:A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. 1240 27

Obesity-prone (AKR/J) and obesity-resistant (SWR/J) mice were weaned onto low (LF) or high fat (HF) diets to identify adaptive changes in adipocyte gene expression that are associated with differences between the strains in fat deposition. Food consumption was monitored at weekly intervals and all mice were evaluated after consuming their respective diets for 4 wk for analysis of mRNA levels of selected metabolic genes. Despite similar food consumption, body weight and fat deposition were significantly greater in AKR/J than in SWR/J mice, and this difference was greatly accentuated by the HF diet. The HF diet produced distinct differences between strains in gene expression patterns among fat depots. In AKR/J mice, UCP1 mRNA was decreased 10-fold in interscapular brown adipose tissue (BAT) and four- to fivefold in retroperitoneal and inguinal white adipose tissue (WAT). The HF diet also decreased PGC-1 and beta(3)-adrenergic receptor mRNA by two- and ninefold in BAT from AKR/J mice. In contrast, the HF diet either increased uncoupling protein (UCP)1 in BAT or had no effect on expression of these genes in adipose tissues from SWR/J mice. UCP2 mRNA was fourfold higher in WAT from AKR/J compared with SWR/J mice and increased by an additional twofold in WAT from AKR/J mice fed the HF diet. UCP2 was unaffected by diet in SWR/J mice. These studies show that the diet-induced obesity of AKR/J mice is characterized by increased metabolic efficiency and is associated with changes in adipocyte gene expression that limit the adaptive thermogenic response to increased energy density.
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PMID:Adaptive changes in adipocyte gene expression differ in AKR/J and SWR/J mice during diet-induced obesity. 1242 46

Obesity is a major risk factor associated with a variety of human disorders. While its involvement in disorders such as diabetes, coronary heart disease and cancer have been well characterized, it remains to be determined if obesity has a detrimental effect on the nervous system. To address this issue we determined whether obesity serves as a risk factor for neurotoxicity. Model neurotoxicants, methamphetamine (METH) and kainic acid (KA), which are known to cause selective neurodegeneration of anatomically distinct areas of the brain, were evaluated using an animal model of obesity, the ob/ob mouse. Administration of METH and KA resulted in mortality among ob/ob mice but not among their lean littermates. While METH caused dopaminergic nerve terminal degeneration as indicated by decreased striatal dopamine (49%) and tyrosine hydroxylase protein (68%), as well as an increase in glial fibrillary acidic protein by 313% in the lean mice, these effects were exacerbated under the obese condition (96%, 86% and 602%, respectively). Similarly, a dosage of KA that did not increase glial fibrillary acidic protein in lean mice increased the hippocampal content of this protein (93%) in ob/ob mice. KA treatment resulted in extensive neuronal degeneration as determined by Fluoro-Jade B staining, decreased hippocampal microtubule-associated protein-2 immunoreactivity and increased reactive gliosis in ob/ob mice. The neurotoxic outcome in ob/ob mice remained exacerbated even when lean and ob/ob mice were dosed with METH or KA based only on a lean body mass. Administration of METH or KA resulted in up-regulation of the mitochondrial uncoupling protein-2 to a greater extent in the ob/ob mice, an effect known to reduce ATP yield and facilitate oxidative stress and mitochondrial dysfunction. These events may underlie the enhanced neurotoxicity seen in the obese mice. In summary, our results implicate obesity as a risk factor associated with chemical- and possibly disease-induced neurodegeneration.
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PMID:Obesity exacerbates chemically induced neurodegeneration. 1245 1

The brown adipose tissue (BAT) thermogenic response to diet-induced obesity and cold has been found to be gender dependent. In the present work, we aimed to investigate the effects of the main physiological male and female sex hormones, i.e. testosterone, progesterone and 17-beta-estradiol, on the expression of uncoupling protein I (UCP1)--the main mediator of BAT thermogenesis--and on UCP2 and lipid accumulation in rodent brown adipocytes differentiated in culture. Testosterone-treated cells showed fewer and smaller lipid droplets than control cells and a dose-dependent inhibition of UCP1 mRNA expression, under adrenergic stimulation by norepinephrine (NE). These effects were reverted by the androgen receptor antagonist flutamide, suggesting they are dependent, at least in part, on the androgen receptor. Progesterone- and 17-beta-estradiol-treated cells showed more and larger lipid droplets and progesterone stimulated NE-induced UCP1 mRNA expression at the lower concentration tested, but not at higher concentrations, suggesting that for brown adipocytes, this hormone is dose dependent. 17-beta-Estradiol did not have any remarkable effect either on UCP1 or UCP2 mRNA expression. Interestingly, the specific progesterone receptor antagonist RU486 induced UCP1 and UCP2 mRNAs, including UCP1 mRNA expression in non-NE-treated brown adipocytes, suggesting a profound effect of this antiprogestagen on brown adipocyte thermogenic capacity. Thus, are conclude that testosterone, 17-beta-estradiol, progesterone and RU486 have distinct actions on brown adipocytes, thus modulating UCP1 and UCP2 mRNA expression and/or lipid accumulation, and that sex hormones are factors that may explain in part the gender-dependent BAT thermogenic response.
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PMID:Opposite actions of testosterone and progesterone on UCP1 mRNA expression in cultured brown adipocytes. 1247 82

Stable free radical nitroxides are potent antioxidants possessing superoxide dismutase- and catalase-mimetic activity that protect cells and animals against a variety of oxidative insults. Tempol, as a representative nitroxide, was evaluated for its influence on weight maintenance and spontaneous tumor incidence in C3H mice. Tempol administered in either the drinking water or food did not show any untoward effects and prevented animals from becoming obese. Tempol-treated animals' leptin levels were reduced. Long-term treatment with Tempol significantly decreased tumorigenesis when compared to controls (10 vs. 40%, respectively). Selected tissues from Tempol-treated animals exhibited elevated levels of mitochrondrial uncoupling protein-2 (UCP-2) and HSP70. The present data suggest that nitroxides upregulate UCP-2, obviate weight gain, and decrease age-related spontaneous tumor incidence. As a class, nitroxides may provide overall health benefits by contributing to decreased obesity and tumor incidence.
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PMID:A low molecular weight antioxidant decreases weight and lowers tumor incidence. 1249 84

The scientifically novel, but evolutionarily ancient, so-called uncoupling proteins 2 and 3 (UCP2, UCP3) are structurally similar to the archetypical uncoupling protein UCP1. A series of suggestions have been forwarded for their physiological function. We discuss systematically here the pros and cons for these suggestions. We conclude that the novel UCPs do not seem to be physiologically relevant uncoupling proteins; the uncoupling property was apparently a late introduction into the subfamily through the evolution of UCP1. Physiological functions ascribed to UCP2 and UCP3 based on their purported uncoupling property may have to be revised (i.e. any type of thermogenesis, including protection against obesity, protection against the formation of reactive oxygen species and thermogenic involvement in the fever response). The presence of a mixed genetic background in most published studies of UCP2 or UCP3 gene-ablated mice also means that data concerning marked differences in diabetes propensity, infection sensitivity and production of reactive oxygen species may require confirmation in backcrossed mice. The increased expression of UCP2 and UCP3 under conditions of increased fatty acid metabolism implies an as yet undefined role in lipid metabolism. Thus, the novel UCPs should probably be considered as mitochondrial carriers, and the challenge now is to identify the transported molecule.
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PMID:The 'novel' 'uncoupling' proteins UCP2 and UCP3: what do they really do? Pros and cons for suggested functions. 1252 56


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