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)

Uncoupling proteins are mitochondrial carrier proteins that catalyse a regulated proton leak across the inner mitochondrial membrane, diverting free energy from ATP synthesis by the mitochondrial F0F1-ATP synthase to the production of heat. Uncoupling protein 1 (UCP1), which is exclusively expressed in brown adipose tissue, is the mediator of thermogenesis in response to beta-adrenergic stimulation. Using gene a knockout mouse model, UCP1 has been shown to be required for cold acclimation. Two homologues of UCP1, UCP2 and UCP3, have been identified recently and show a much wider tissue distribution. UCP2 and UCP3 have been postulated to play a role in the regulation of cold acclimation, energy expenditure and diet-induced thermogenesis in humans, who, in contrast to rodents, have very little brown fat in adult life. However, evidence is accumulating that thermogenesis and regulation of body weight may not be the physiological functions of UCP2 and UCP3. For instance, mice deficient for UCP2 or UCP3 are not cold-intolerant and do not develop obesity. Alternative functions were suggested, primarily based on findings in UCP2 and UCP3 gene knockout mice. Both UCP2- and UCP3-deficient mice were found to overproduce reactive oxygen species and UCP2-deficient mice to hypersecrete insulin. Thus, the UCP1 homologues may play a role in regulating mitochondrial production of reactive oxygen species and b-cell function. In this review, we discuss the role of UCP1, UCP2 and UCP3 in human physiology and disease, primarily based on findings from the various animal models that have been generated.
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PMID:Mitochondrial uncoupling proteins in human physiology and disease. 1185 Jun 13

Elevated islet uncoupling protein-2 (UCP-2) impairs beta-cell function and UCP-2 may be increased in clinical obesity and diabetes. We investigated the effects of glucose and leptin on UCP-2 expression in isolated human islets. Human islets were incubated for 24 h with glucose (5.5-22 mmol/l)+/-leptin (0-10 nmol/l). Some islet batches were incubated at high (22 mmol/l), and subsequently lower (5.5 mmol/l), glucose to assess reversibility of effects. Leptin effects on insulin release were also measured. Glucose dose-dependently increased UCP-2 expression in all islet batches, maximally by three-fold. This was not fully reversed by subsequently reduced glucose levels. Leptin decreased UCP-2 expression by up to 75%, and maximally inhibited insulin release by 47%, at 22 mmol/l glucose. This is the first report of UCP-2 expression in human islets and provides novel evidence of its role in the loss of beta-cell function in diabetes.
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PMID:Glucose induces and leptin decreases expression of uncoupling protein-2 mRNA in human islets. 1190 48

Nonalcoholic fatty liver disease (NAFLD), a prevalent condition associated with obesity, has the potential of evolving into end-stage liver disease. The biochemical mechanisms that define the progression of NAFLD are not well known, but reactive oxygen species (ROS) have been implicated in this process. Uncoupling protein (UCP) 2 is a mitochondrial inner-membrane protein that mediates proton leak, uncouples adenosine triphosphate (ATP) synthesis, and negatively regulates ROS production. UCP2 expression is increased in various animal models of NAFLD. Up-regulation of UCP2 may compromise cellular ATP levels and worsen liver damage, or it may be protective by ROS reduction in NAFLD. This study aimed to obtain a definitive answer as to whether increased UCP2 expression contributes to NAFLD. UCP2-/- mice were exposed to obesity by crossbreeding with ob/ob mice and by long-term high-fat feeding to study the effect of UCP2 deficiency on the outcome of NAFLD. Steatohepatitis score of crossbred mice (ob/ob/ko) was similar to that of ob/ob mice at 25 weeks. No compensatory increase was observed in the expression of UCP5 in ob/ob/ko livers. To unmask the effects of absent leptin and its potential proinflammatory actions, steatosis was also induced in UCP2-/- mice by a high-fat diet continued for 6 months. Serum alanine aminotransferase (ALT) levels remained normal, and the steatohepatitis score in UCP2-/- mice was the same as in wild-type controls. We conclude that increased expression of UCP2 in the livers of mice with genetically or diet-induced obesity exerts neither protective nor deleterious effects on the severity of fatty liver disease.
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PMID:Obesity-related fatty liver is unchanged in mice deficient for mitochondrial uncoupling protein 2. 1191 20

Neuropeptide Y (NPY), a peptide released by nervous cells, appears to contribute to adiposity regulation by increasing food intake and inhibiting lipolysis. New NPY receptor related antagonists such as S.A.0204 are being developed as potential anti-obesity drugs affecting adipocyte lipid metabolism and thermogenesis. In this sense, those animals fed on a high-energy yielding (cafeteria) diet decreased body fat weight as compared to overweight controls, when they were administered with S.A.0204, and increased body temperature, which statistically correlated with high UCP2 mRNA expression levels in white adipose tissue. In addition, the in vivo NPY-antagonist administration was able to prevent white adipose tissue growth in animals fed the cafeteria (high-fat) diet by impairing PPARy and CIEBPalpha mRNA expression in white fat cells. In summary, this novel NPY related-antagonist S.A.0204 may regulate body fat deposition by affecting both energy dissipation and white adipose tissue deposition, representing a potential new pharmacological strategy for obesity management.
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PMID:Changes in UCP2, PPARgamma2, and c/EBPalpha gene expression induced by a neuropeptide Y (NPY) related receptor antagonist in overweight rats. 1192 93

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

In mammals, methionine metabolism occurs mainly in the liver via methionine adenosyltransferase-catalyzed conversion to S-adenosylmethionine. Of the two genes that encode methionine adenosyltransferase(MAT1Aand MAT2A), MAT1A is mainly expressed in adult liver whereas MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic S-adenosylmethionine content and hyperplasia and spontaneously develop nonalcoholic steatohepatitis. In this study, we examined whether chronic hepatic S-adenosylmethionine deficiency generates oxidative stress and predisposes to injury and malignant transformation. Differential gene expression in MAT1A knockout mice was analyzed following the criteria of the Gene Ontology Consortium. Susceptibility of MAT1A knockout mice to CCl4-induced hepatotoxicity and malignant transformation was determined in 3- and 18-month-old mice, respectively. Analysis of gene expression profiles revealed an abnormal expression of genes involved in the metabolism of lipids and carbohydrates in MAT1A knockout mice, a situation that is reminiscent of that found in diabetes, obesity, and other conditions associated with nonalcoholic steatohepatitis. This aberrant expression of metabolic genes in the knockout mice was associated with hyperglycemia, increased hepatic CYP2E1 and UCP2 expression and triglyceride levels, and reduced hepatic glutathione content. The knockout animals have increased lipid peroxidation and enhanced sensitivity to CCl4-induced liver damage, which was largely due to increased CYP2E1 expression because diallyl sulfide, an inhibitor of CYP2E1, prevented CCl4-induced liver injury. Hepatocellular carcinoma developed in more than half of the knockout mice by 18 months of age. Taken together, our findings define a critical role for S-adenosylmethionine in maintaining normal hepatic function and tumorigenesis of the liver.
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PMID:Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. 1206 Jun 74

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


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