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)

Fish oil feeding showed less obesity in rodents, relative to other dietary oils. N-3 fatty acids rich in fish oil and fibrate compounds are peroxisome proliferator-activated receptor alpha (PPARalpha) ligands that stimulate beta-oxidation of fatty acids in liver and are used for treatment of hypertriglycemic patients. Since UCP-2, a member of an uncoupling protein family, has been shown to express in hepatocytes, the effects of these agents on the expression of UCP2 mRNA were investigated. C57BL/6J mice were divided into three groups; the first group was given a high-carbohydrate diet, and the other two groups were given a high-fat diet (60% of total energy) as safflower oil or fish oil for 5 months. Safflower oil diet fed mice developed obesity, but those fed fish oil diet did not. Therefore, the effects of fish oil feeding on the expression of UCP1, UCP2 and UCP3 in liver, skeletal muscle (gastrocnemius), white adipose tissue (WAT) and brown adipose tissue (BAT) were assessed by Northern blotting. Compared with safflower oil feeding, fish oil feeding up-regulated liver UCP2, BAT UCP2 and skeletal muscle UCP3 mRNA, while down-regulated WAT UCP2 and BAT UCP3 mRNA. Among these alterations, 5-fold up-regulation of liver UCP2 mRNA, relative to carbohydrate feeding, was noteworthy. Fenofibrate administration (about 500 mg/kg BW/d) for 2 wks also induced liver UCP2 expression by 9-fold. These data indicated that fish oil feeding and fibrate administration each up-regulated UCP2 mRNA expression in liver possibly via PPARalpha and hence each has the potential of increasing energy expenditure for prevention of obesity.
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PMID:Up-regulation of liver uncoupling protein-2 mRNA by either fish oil feeding or fibrate administration in mice. 1020 78

It has been claimed that factors favoring the development or maintenance of animal or human obesity may include increases in glucocorticoid production or hyperresponsiveness of the hypothalamic-pituitary-adrenal axis. In normal rats, glucocorticoids have been shown to be necessary for chronic intracerebroventricular infusion of neuropeptide Y to produce obesity and related abnormalities. Conversely, glucocorticoids inhibited the body weight-lowering effect of leptin. Such dual action of glucocorticoids may occur within the central nervous system, since both neuropeptide Y and leptin act within the hypothalamus. The aim of this study was to determine the effects of glucocorticoids (dexamethasone) given intracerebroventricularly to normal rats on body weight homeostasis and hypothalamic levels of neuropeptide Y and corticotropin-releasing hormone. Continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion abolished endogenous corticosterone output and produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and UCP-3 in muscle. Finally, chronic central glucocorticoid administration increased the hypothalamic levels of neuropeptide Y and decreased those of corticotropin-releasing hormone. When the same dose of glucocorticoids was administered peripherally, it resulted in decreases in food intake and body weight, in keeping with the decrease in hypothalamic neuropeptide Y levels. These results suggest that glucocorticoids induce an obesity syndrome in rodents by acting centrally and not peripherally.
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PMID:Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat. 1033 15

It has been reported that hyperphagia and excessive body weight gain of genetically obese rodents were abolished by adrenalectomy. High hypothalamic levels of neuropeptide Y (NPY) were found in obese rodents. A chronic intracerebroventricular (icv) infusion of NPY in normal rats was shown to produce most hormono-metabolic abnormalities of genetically obese animals, and to be inefficient in doing so in adrenalectomized (ADX) rats. The combined presence of NPY and of glucocorticoids thus appeared to be necessary for inducing obesity. This study, therefore, was aimed at determining the consequences of a chronic i.c.v. NPY infusion in ADX rats receiving or not i.c.v. glucocorticoids. It was found that the combined i.c.v. infusion of NPY and dexamethasone in ADX rats increased food intake, body weight, plasma insulin, leptin, and triglyceride levels relative to vehicle-infused ADX controls. The infusion of NPY alone, or of dexamethasone alone in ADX rats failed to produce these effects. In contrast, the icv infusion of NPY alone greatly decreased the expression of brown adipose tissue uncoupling protein-1 and -3. This was not modified by the superimposed infusion of dexamethasone. It is concluded that, although many of centrally elicited NPY effects require the central presence of glucocorticoids, those bearing on the inhibition of uncoupling proteins expression (energy dissipation) do not require central glucocorticoids.
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PMID:Selective dependence of intracerebroventricular neuropeptide Y-elicited effects on central glucocorticoids. 1038 13

Thermogenesis is associated to oxygen consumption and cellular respiration. This process is coupled to adenosine-diphosphate (ADP) phosphorylation through the existence of a proton gradient across the inner mitochondrial membrane. It was postulated that proton leaks through this membrane would uncouple respiration from adenosine-triphosphate (ATP) synthesis and induce energy dissipation as heat. Such a mechanism was identified in thermogenic brown adipose tissue mitochondria which contain a unique proton carrier referred to as uncoupling protein (UCP). This UCP is activated by fatty acids and its synthesis is positively controlled by retinoids, thyroid hormones, catecholamines and rexinoids. In fact, in most types of cells, respiring mitochondria release heat and the coupling of substrate oxidation to ADP phosphorylation is under 100%. It suggested that the partial coupling of respiration to ADP phosphorylation was due to proton leaks possibly related to the brown fat UCP. This approach led to the identification of UCP2 and UCP3, two homologues of the brown fat UCP (renamed UCP1). UCP2 gene is widely expressed in tissues and cell types, whereas the UCP3 gene is dominantly expressed in skeletal muscles (and brown fat in mice). Recent genetic, biochemical and physiological studies suggest that these novel UCP2 contribute to resting metabolic rate, fat oxidation and may represent new targets for anti-obesity compounds.
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PMID:Uncoupling protein-2 (UCP2): molecular and genetic studies. 1045 20

Uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) are mitochondrial proteins that may play a role in the control of energy expenditure by uncoupling respiration from ATP synthesis. The present review focuses on data obtained in humans. UCP2 is widely expressed in the body, whereas UCP3 expression is restricted to skeletal muscle. Positive correlations have been reported between UCP2 mRNA concentrations in adipose tissue, UCP3 mRNA concentrations in skeletal muscle, and components of the metabolic rate. Fasting induces an up-regulation of UCP2 and UCP3 mRNA expression. In vivo and in vitro studies suggest that fatty acids could modulate uncoupling protein gene expression. The putative relationship between obesity, energy expenditure and uncoupling protein expression, and the unexpected rise in UCP2 and UCP3 mRNA concentrations during short-term fasting, are discussed in view of the recent data obtained in rodents and cell lines.
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PMID:Uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) expression in adipose tissue and skeletal muscle in humans. 1045 28

By virtue of its potential effects on rates of energy expenditure, uncoupling protein 3 (UCP3) is an obesity candidate gene. We identified nine sequence variants in UCP3, including Val9Met, Val102Ile, Arg282Cys, and a splice site mutation in the intron between exons 6 and 7. The splice mutation results in an inability to synthesize mRNA for the long isoform (UCP3L) of UCP3. Linkage (sib pair), association, and transmission disequilibrium testing studies on 942 African-Americans did not suggest a significant effect of UCP3 on body composition in this group. In vastus lateralis skeletal muscle of individuals homozygous for the splice mutation, no UCP3L mRNA was detectable; the short isoform (UCP3S) was present in an increased amount. In this muscle, we detected no alterations of in vitro mitochondrial coupling activity, mitochondrial respiratory enzyme activity, or systemic oxygen consumption or respiratory quotient at rest or during exercise. These genetic and physiologic data suggest the following possibilities: UCP3S has uncoupling capabilities equivalent to UCP3L; other UCPs may compensate for a deficiency of bioactive UCP3L; UCP3L does not function primarily as a mitochondrial uncoupling protein.
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PMID:Genetic and physiologic analysis of the role of uncoupling protein 3 in human energy homeostasis. 1048 Jun 26

We investigated the effect of long-term administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E), an n-3 polyunsaturated fatty acid derived from fish oil, in comparison to lard on the development of hypertension and insulin resistance in Dahl salt-sensitive (Dahl-S) rats fed a high-sucrose diet (HSD), a model of salt-sensitive hypertension. After 16 weeks of treatment, the glucose infusion rate (GIR) during the euglycemic insulin-glucose clamp test significantly increased in the HSD-EPA-E group compared with the HSD-water or -lard control group. The GIR was approximately three times higher in the HSD-EPA-E group versus the HSD-water or -lard control group, and it was about 70% of the rate in the calorically deprived control group fed a low-fat-high-fiber diet (LF-HFD). In addition, EPA-E significantly suppressed the elevation of plasma glucose and insulin levels after oral glucose loading. These results indicate that EPA-E prevents the development of insulin resistance in Dahl-S rats fed a HSD. Fatty acid analysis of phospholipids in skeletal muscle showed a significant increase in C18:2, C20:5, and C22:5 components in the HSD-EPA-E group and, conversely, a significant decrease in C16:0, C20:4, and C22:6. The present results indicate that the beneficial effect of EPA-E on insulin resistance in Dahl-S rats fed a HSD is likely dependent on the modification of phospholipid components in the skeletal muscle membrane. These findings suggest that EPA-E might prevent the development of insulin resistance in dietary obesity. In addition, the HSD-EPA-E group showed a significant increase in the level of uncoupling protein (UCP) in brown adipose tissue as compared with the HSD-water or -lard control group. However, EPA-E had no effect on the development of hypertension and obesity in Dahl-S rats fed the HSD.
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PMID:Effect of highly purified eicosapentaenoic acid ethyl ester on insulin resistance and hypertension in Dahl salt-sensitive rats. 1048 46

Genetically determined obesities, involving leptin- and melanocortin-signaling pathways, have focused attention on the four medial hypothalamic nuclei as primary sources of feeding- and metabolically-based obesity. All four medial cell groups contain leptin receptors. To determine which of these cell groups normally mediates the effects of leptin on food intake and body weight gain, we injected colchicine bilaterally into each nucleus and determined the pathophysiological effects of disruption and responsivity to leptin injected intracerebroventricularly. Intracerebroventricular injections of leptin in sham-lesioned rats decreased food intake during the dark period, but not during the light period. Lesions of the arcuate (ARC), paraventricular (PVN), and ventromedial (VMN) nuclei all resulted in leptin insensitivity; by contrast, lesions of the dorsomedial nuclei (DMN) augmented sensitivity to leptin on feeding and body weight gain. Although rats with ARC and PVN lesions were obese, they were still capable of reducing caloric efficiency over the 5 days of study and increasing uncoupling protein content in interscapular brown adipose tissue. Caloric efficiency and uncoupling protein content were unchanged in rats with VMN and DMN lesions. Finally, the slope of the relationship between leptin and mesenteric white adipose tissue was increased in rats with VMN lesions and abolished in rats with ARC lesions. Thus, lesions of the ARC, PVN, and VMN produced obesity via separate pathways. We conclude that the medial hypothalamic cell groups, each with a different role in energy balance, are all necessary for normal leptin responsiveness.
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PMID:Rats with hypothalamic obesity are insensitive to central leptin injections. 1049 95

Brown adipose and muscle tissues can increase energy expenditure via adaptive thermogenesis, thereby protecting against obesity. Mouse peroxisome proliferator activated receptor gamma coactivator 1 (Pgc1) has been reported to enhance the expression of uncoupling protein-1, a key mediator of thermogenesis in brown adipose tissue (Puigserver et al., 1998, Cell 92, 829-839). We report here the characterization of the human PPARGC1 gene. PPARGC1 spans a genomic region of approximately 67 kb, is composed of 13 exons, and encodes a 91-kDa protein that exhibits 94% amino acid identity with the mouse ortholog. mRNA species, transcribed from the TATA-less promoter, are 6.4 and 5.3 kb in length due to utilization of two polyadenylation signals. Northern blotting revealed expression of both transcripts in heart, skeletal muscle, and kidney and to a lesser extent in liver, brain, and pancreas as well as in the perirenal adipose tissue of a pheochromocytoma patient. PPARGC1 was mapped to chromosome 4p15.1, a region that has been associated with basal insulin levels in Pima Indians. Hence, PPARGC1 expression might influence insulin sensitivity as well as energy expenditure, thereby contributing to the development and pathophysiology of human obesity.
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PMID:Human peroxisome proliferator activated receptor gamma coactivator 1 (PPARGC1) gene: cDNA sequence, genomic organization, chromosomal localization, and tissue expression. 1058 75

In eukaryotic cells ATP is generated by oxidative phosphorylation, an energetic coupling at the mitochondrial level. The oxidative reactions occurring in the respiratory chain generate an electrochemical proton gradient on both sides of the inner membrane. This gradient is used by the ATPsynthase to phosphorylate ADP into ATP. The coupling between respiration and ADP phosphorylation is only partial in brown adipose tissue (BAT) mitochondria, where the uncoupling protein UCP1 causes a reentry of protons into the matrix and abolishes the electrochemical proton gradient. The liberated energy is then dissipated as heat and ATP synthesis is reduced. This property was for a long time considered as an exception and specific to the non-shivering thermogenesis found in BAT. The recent cloning of new UCPs expressed in other tissues revealed the importance of this kind of regulation of respiratory control in metabolism and energy expenditure. The newly characterised UCPs are potential targets for obesity treatment drugs which could favour energy expenditure and diminish the metabolic efficiency. In 1997, we cloned UCP2 and proposed a role for this new uncoupling protein in diet-induced thermogenesis, obesity, hyperinsulinemia, fever and resting metabolic rate. Currently, an abundant literature deals with UCP2, but its biochemical and physiological functions and regulation remain unclear. The present review reports the status of our knowledge of this mitochondrial carrier in terms of sequence, activity, tissue distribution and regulation of expression. The putative physiological roles of UCP2 will be introduced and discussed.
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PMID:The mitochondrial uncoupling protein-2: current status. 1060 19


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