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 effects of a 3-d peripheral administration of an alpha-MSH agonist, MTII, on body weight and the expression of uncoupling proteins (UCPs) and carnitine palmitoyltransferase-1 were determined in lean and genetically obese fa/fa rats by comparing MTII-treated animals with two different control groups, one being ad libitum fed, the other pair-fed to the amount of food consumed by MTII-treated rats. MTII treatment of lean and obese rats lowered food intake and body weight, the effects being more marked in obese than in lean rats. In both groups, MTII administration suppressed the increased plasma FFA levels brought about by food restriction. In lean rats, MTII prevented the decrease in brown adipose tissue UCP1, UCP2, and UCP3 expression and muscle UCP3 occurring during food restriction. In obese animals, MTII markedly increased brown adipose tissue (7-fold) and muscle (2.5-fold) UCP3 expression. The decrease in liver carnitine palmitoyltransferase-1 elicited by food restriction in lean and obese rats was prevented by MTII administration. In summary, the effects of MTII resemble those of leptin and are more marked in obese than in lean animals, in keeping with their reported reduced endogenous melanocortin tone. Melanocortin agonists may be useful in the treatment of obesity associated with impaired leptin signaling.
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PMID:The leptin-like effects of 3-d peripheral administration of a melanocortin agonist are more marked in genetically obese Zucker (fa/fa) than in lean rats. 1202 Nov 92

Until very recently, the uncoupling protein-1 (UCP1), present only in brown adipose tissue (BAT), was considered to be the only mitochondrial carrier protein that stimulated heat production by dissipating the proton gradient generated during respiration across the inner mitochondrial membrane and therefore uncoupling respiration from ATP synthesis. Recently, new uncoupling proteins, UCP2, UCP3, and UCP4, and brain mitochondrial carrier protein-1 (BMCP-1) have been described in mammalian tissues. The present review deals with the possible role of these proteins in different pathological conditions involving alterations in energy balance such as obesity or cachexia. In conclusion, the emergence of the UCP family has altered the approaches to bioenergetics and stressed the importance of uncoupling respiration in different pathophysiological conditions. An extensive qualitative and quantitative characterization of the new members of the UCP family in mammalian tissues will allow a better understanding of the molecular and regulatory mechanisms of thermogenesis and energy metabolism. At this point, we hope that the knowledge presented in the present review will not only stimulate a debate about the role of the UCP family in disease but also lead to applications beneficial for human health.
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PMID:The role of uncoupling proteins in pathophysiological states. 1205 95

It is becoming evident that insulin resistance of white adipose tissue is a major factor underlying the cardiovascular risk of obesity. Impaired fat storage rather than altered glucose metabolism in adipocytes probably contributes to development of insulin resistance in muscle and other tissues, in particular via increased delivery of nonesterified fatty acids into circulation. Lipid metabolism of adipose tissue is affected by the energy status of fat cells. In vitro experiments indicated the dependence of both lipogenesis and lipolysis on ATP levels in adipocytes. Thus, respiratory uncoupling in adipocytes that results in stimulation of energy dissipation and depression of ATP synthesis may contribute to the control of lipid metabolism, adiposity, and insulin sensitivity. This notion is supported by the expression of UCPs in adipocytes, for example, UCP2, UCP5, as well as some protonophoric anion transporters, and by induction of UCP1 and UCP3 in white fat by pharmacological treatments that reduce adiposity. A negative correlation between expression of UCPs in adipocytes and accumulation of white fat was also found. Expression of UCP1 from the adipose-specific promoter in the aP2-Ucp1 transgenic mice mitigated obesity induced by genetic or dietary factors. The obesity resistance, accompanied by respiratory uncoupling in adipocytes and increased energy expenditure, resulted from ectopic expression of UCP1 in white, but not brown fat. Probably due to depression of the ATP/ADP ratio, both fatty acid synthesis and lipolytic action of norepinephrine in adipocytes of transgenic mice were relatively low. Expression of regulatory G-proteins, which are essential for both catecholamine and insulin signaling in adipocytes, was also altered by ectopic UCP1. These results support the role of protonophoric proteins in adipocytes in the control of adiposity and insulin sensitivity. Antidiabetic effects of thiazolidinediones, fibrates, beta(3)-adrenoreceptor agonists, dietary n-3 PUFAs, and leptin may be explained at least partially by their effects on the energy and hence also the lipid metabolism of fat cells.
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PMID:Modulation of lipid metabolism by energy status of adipocytes: implications for insulin sensitivity. 1207 39

The uncoupling protein-1 (UCP1) homologues UCP2 and UCP3 are able to uncouple ATP production from mitochondrial respiration, thereby dissipating energy as heat and affecting energy metabolism efficiency. In contrast to UCP1, which plays an important role in adaptive thermogenesis, UCP2 and UCP3 do not have a primary role in the regulation of energy metabolism. UCP2, which is expressed in a wide variety of tissues, including white adipose tissue, skeletal muscle and tissues of the immune system, has been suggested to affect the production of reactive oxygen species. UCP2 has also been suggested to regulate the [ATP]/[ADP] ratio and was recently shown to influence insulin secretion in the beta-cells of the pancreas. UCP3, in contrast, is expressed predominantly in skeletal muscle and has been associated with whole-body energy metabolism. However, the primary function of UCP3 is not the regulation of energy metabolism. For example, fasting, a condition attenuating energy expenditure, upregulates UCP3 expression. Moreover, UCP3-knockout mice have a normal metabolic rate. The exact function of UCP3 therefore remains to be elucidated, but putative roles for UCP3 include involvement in the regulation of ROS, in mitochondrial fatty acid transport and in the regulation of glucose metabolism in skeletal muscle. Whatever the primary function of these novel uncoupling proteins, a secondary effect via uncoupling might allow them to influence (but not to regulate) energy metabolism, which would be consistent with the observations from linkage and association studies. Therefore, UCP2 and UCP3 remain interesting targets for pharmacological upregulation in the treatment of obesity and diabetes.
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PMID:UCP2 and UCP3 in muscle controlling body metabolism. 1211 Jun 61

Mitochondrial proton cycling is responsible for a significant proportion of basal or standard metabolic rate, so further uncoupling of mitochondria may be a good way to increase energy expenditure and represents a good pharmacological target for the treatment of obesity. Uncoupling by 2,4-dinitrophenol has been used in this way in the past with notable success, and some of the effects of thyroid hormone treatment to induce weight loss may also be due to uncoupling. Diet can alter the pattern of phospholipid fatty acyl groups in the mitochondrial membrane, and this may be a route to uncoupling in vivo. Energy expenditure can be increased by stimulating the activity of uncoupling protein 1 (UCP1) in brown adipocytes either directly or through beta 3-adrenoceptor agonists. UCP2 in a number of tissues, UCP3 in skeletal muscle and the adenine nucleotide translocase have also been proposed as possible drug targets. Specific uncoupling of muscle or brown adipocyte mitochondria remains an attractive target for the development of antiobesity drugs.
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PMID:Mitochondrial uncoupling as a target for drug development for the treatment of obesity. 1211 96

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

The "thrifty" genotype and phenotype that save energy are detrimental to the health of people living in affluent societies. Individual differences in energy metabolism are caused primarily by single nucleotide polymorphisms (SNPs), some of which promote the development of obesity/type 2 diabetes mellitus. In this review, four major questions are addressed: (1) Why did regional differences in energy metabolism develop during evolution? (2) How do genes respond to starvation and affluence? (3) Which SNPs correspond to the hypothetical "thrifty genes"? (4) How can we cope with disease susceptibility caused by the "thrifty" SNPs? We examined mtDNA and genes for energy metabolism in people who live in several parts of Asia and the Pacific islands. We included 14 genes, and the SNP frequencies of PPAR gamma 2, LEPR, and UCP3-p and some other genes differ significantly between Mongoloids and Caucasoids. These differences in SNPs may have been caused by natural selection depending on the types of agriculture practiced in different regions. Interventions to counteract the adverse effects of "thrifty" SNPs have been partially effective.
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PMID:Single nucleotide polymorphisms of thrifty genes for energy metabolism: evolutionary origins and prospects for intervention to prevent obesity-related diseases. 1215 Sep 34

To establish whether changes in skeletal muscle mitochondrial efficiency contribute to increased energy expenditure and decreased metabolic efficiency of overeating rats with increased thermogenesis, we measured basal proton leak, fatty acid-induced uncoupling and uncoupling protein 3 (UCP3) content in subsarcolemmal and intermyofibrillar skeletal muscle mitochondria. Intermyofibrillar, but not subsarcolemmal, mitochondria from rats with increased thermogenesis exhibited a lower proton leak compared with controls. In both mitochondrial populations from rats with increased thermogenesis, fatty acid-induced uncoupling was increased significantly and a small recoupling effect of GDP was detected. In addition, intermyofibrillar and subsarcolemmal mitochondria from rats with increased thermogenesis showed higher UCP3 contents than controls. These results point out that metabolic efficiency in subsarcolemmal and intermyofibrillar mitochondria from rats with increased thermogenesis is differently regulated. In fact, in intermyofibrillar mitochondria both basal proton leak and fatty acid-induced uncoupling are altered, while in subsarcolemmal mitochondria only fatty acid-induced uncoupling increases. Both mitochondrial populations in skeletal muscle cells from rats with increased thermogenesis display an increased fatty acid-induced uncoupling and UCP3 content, which could contribute to avoiding obesity.
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PMID:Skeletal muscle mitochondrial efficiency and uncoupling protein 3 in overeating rats with increased thermogenesis. 1246 47

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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