Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Impaired activity of the uncoupling protein (UCP) family has been proposed to promote obesity development. The present study examined differences in UCP responses to cold exposure between leptin-resistance obese (db/db) mice and their lean (C57Ksj) littermates. Basal UCP1 and UCP3 mRNA expression in brown adipose tissue was lower in obese mice compared with lean mice, but UCP2 expression in white adipose tissue (WAT) was higher. Basal skeletal muscle UCP3 did not change remarkably. The UCP family mRNAs, which were upregulated 12 and 24 h after cold exposure (4 degrees C), were returned to prior levels 12 h after rewarming exposure (21 degrees C) in lean mice. The accelerating effects of cold exposure on the UCP family were impaired in db/db obese mice. Together with these changes, WAT lipoprotein lipase mRNA was downregulated, and the concentration of serum free fatty acid was increased in response to cold exposure in the lean mice but not in db/db obese littermates. The impaired function of the UCP family and diminished lipolysis in response to cold exposure indicate that the reduced lipolytic activity may contribute to the inactivation of the UCP family in db/db obese mice.
 ...
PMID:Impaired response of UCP family to cold exposure in diabetic (db/db) mice. 1100 97

The coupling of oxygen consumption to ADP phosphorylation is incomplete, as is particularly evident in brown adipocyte mitochondria which use a regulated uncoupling mechanism to dissipate heat produced by substrate oxidation. In brown adipose tissue, uncoupling is effected by a specific protein in the inner mitochondrial membrane referred to as uncoupling protein-1 (UCP1). UCP1 gene disruption in mice has confirmed UCP1's role in cold-induced thermogenesis. Genetic analysis of human cohorts has suggested that UCP1 plays a minor role in the control of fat content and body weight. The recent cloning of UCP2 and UCP3, two homologues of UCP1, has boosted research on the importance of respiration control in metabolic processes, metabolic diseases and energy balance. UCP2 is widely expressed in different organs whereas UCP3 is mainly present in skeletal muscle. The chromosomal localization of UCP2 as well as UCP2 mRNA induction by a lipid-rich diet in obesity-resistant mice suggested that UCP2 is involved in diet-induced thermogenesis. A strong linkage between markers in the vicinity of human UCP2 and UCP3 (which are adjacent genes) and resting metabolic rate was calculated. UCPs are known or supposed to participate in basal and regulatory thermogenesis, but their exact biochemical and physiological functions have yet to be elucidated. UCPs may constitute novel targets in the development of drugs designed to modulate substrate oxidation. However, very recent data suggest an important role for the UCPs in the control of production of free radicals by mitochondria, and in response to oxidants.
 ...
PMID:Mitochondrial uncoupling proteins: from mitochondria to the regulation of energy balance. 1108 Feb 46

Mitochondrial uncoupling protein (UCP), mitochondrial transporters, function as a proton channel and increase thermogenesis. UCP1 is expressed in brown adipose tissues (BAT), UCP2 is widely expressed in multiple tissues, while UCP3 is expressed in skeletal muscle. Thus, UCPs, especially UCP3, in skeletal muscles is a good candidates for prevention of obesity and diabetes. However, the role of UCP3 in skeletal muscle for energy expenditure and obesity has been controversial. There is some evidence that the UCP3 is possibly regulated by energy substrate, such as lipid and glucose. These observations suggest that increased energy substrate entry in muscle results in an increase in UCP3 expression which leads to an increase in energy expenditure.
 ...
PMID:Mitochondrial uncoupling protein 3 (UCP3) in skeletal muscle. 1122 74

Variability of the uncoupling protein 3 (UCP3) promoter has been associated with increased body mass index (BMI) and altered lipid profiles. Here we tested the hypothesis that variation of the UCP3 promoter is associated with either juvenile or maturity-onset obesity or body weight change over a 26-yr follow-up among Danish subjects. Mutation screening of approximately 1 kb 5' upstream of the UCP3 gene revealed one previously described -55 C-->T variant. The frequency of the polymorphism was evaluated by restriction fragment length polymorphism analysis in four groups of subjects: 1) a group of 744 obese Danish men who at the draft board examinations had a body mass index (BMI) of at least 31 kg/m(2), 2) a randomly selected control group consisting of 857 draftees, 3) 258 middle-aged subjects, and 4) 409 60-yr-old subjects. The frequency of the T allele was 26.0% (95% confidence interval, 23.8-28.2%) among the obese draftees and 26.9% (24.8-29.0%) in the control group (P = 0.6). The variant was not associated with BMI at a young age or with weight gain after a 26-yr follow-up. The frequency of the T allele was 29.5% (25.6-33.4%) in the middle-aged group and 25.8% (22.8-28.8%) among the 60-yr-old subjects. The polymorphism was not associated with increased BMI or percent body fat in these 2 groups. It is concluded that this variant does not play a major role in the development of common obesity among Danish subjects.
 ...
PMID:A prevalent polymorphism in the promoter of the UCP3 gene and its relationship to body mass index and long term body weight change in the Danish population. 1123 38

The uniqueness of UCP1 (as compared to UCP2/UCP3) is evident from expression analysis and ablation studies. UCP1 expression is positively correlated with metabolic inefficiency, being increased by cold acclimation (in adults or perinatally) and overfeeding, and reduced in fasting and genetic obesity. Such a simple relationship is not observable for UCP2/UCP3. Studies with UCP1-ablated animals substantiate the unique role of UCP1: the phenomenon of adaptive adrenergic non-shivering thermogenesis in the intact animal is fully dependent on the presence of UCP1, and so is any kind of cold acclimation-recruited non-shivering thermogenesis; thus UCP2/UCP3 (or any other proteins or metabolic processes) cannot substitute for UCP1 physiologically, irrespective of their demonstrated ability to show uncoupling in reconstituted systems or when ectopically expressed. Norepinephrine-induced thermogenesis in brown-fat cells is absolutely dependent on UCP1, as is the uncoupled state and the recoupling by purine nucleotides in isolated brown-fat mitochondria. Although very high UCP2/UCP3 mRNA levels are observed in brown adipose tissue of UCP1-ablated mice, there is no indication that the isolated brown-fat mitochondria are uncoupled; thus, high expression of UCP2/UCP3 does not necessarily confer to the mitochondria of a tissue a propensity for being innately uncoupled. Whereas the thermogenic effect of fatty acids in brown-fat cells is fully UCP1-dependent, this is not the case in brown-fat mitochondria; this adds complexity to the issues concerning the mechanisms of UCP1 function and the pathway from beta(3)-adrenoceptor stimulation to UCP1 activation and thermogenesis. In addition to amino acid sequences conserved in all UCPs as part of the tripartite structure, all UCPs contain certain residues associated with nucleotide binding. However, conserved amongst all UCP1s so far sequenced, and without parallel in all UCP2/UCP3, are two sequences: 144SHLHGIKP and the C-terminal sequence RQTVDC(A/T)T; these sequences may therefore be essential for the unique thermogenic function of UCP1. The level of UCP1 in the organism is basically regulated at the transcriptional level (physiologically probably mainly through the beta(3)-adrenoceptor/CREB pathway), with influences from UCP1 mRNA stability and from the delay caused by translation. It is concluded that UCP1 is unique amongst the uncoupling proteins and is the only protein able to mediate adaptive non-shivering thermogenesis and the ensuing metabolic inefficiency.
 ...
PMID:UCP1: the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency. 1123 87

The preferential channeling of different fuels to fat and changes in the transcription profile of adipose tissue and skeletal muscle are poorly understood processes involved in the pathogenesis of obesity and insulin resistance. Carbohydrate and lipid metabolism may play relevant roles in this context. Freely moving lean Zucker rats received 3- and 24-h infusions of Intralipid (Pharmacia and Upjohn, Milan, Italy) plus heparin, or saline plus heparin, to evaluate how an increase in free fatty acids (nonesterified fatty acid [NEFA]) modulates fat tissue and skeletal muscle gene expression and thus influences fuel partitioning. Glucose uptake was determined in various tissues at the end of the infusion period by means of the 2-deoxy-[1-3H]-D-glucose technique after a euglycemic-hyperinsulinemic clamp: high NEFA levels markedly decreased insulin-mediated glucose uptake in red fiber-type muscles but enhanced glucose utilization in visceral fat. Using reverse transcriptase-polymerase chain reaction and Northern blotting analyses, the mRNA expression of fatty acid translocase (FAT)/CD36, GLUT4, tumor necrosis factor (TNF)-alpha, peroxisome proliferator-activated receptor (PPAR)-gamma, leptin, uncoupling protein (UCP)-2, and UCP-3 was investigated in different fat depots and skeletal muscles before and after the study infusions. GLUT4 mRNA levels significantly decreased (by approximately 25%) in red fiber-type muscle (soleus) and increased (by approximately 45%) in visceral adipose tissue. Furthermore, there were marked increases in FAT/CD36, TNF-alpha, PPAR-gamma, leptin, UCP2, and UCP3 mRNA levels in the visceral fat and muscle of the treated animals in comparison with those measured in the saline-treated animals. These data suggest that the in vivo gene expression of FAT/CD36, GLUT4, TNF-alpha, PPAR-gamma, leptin, UCP2, and UCP3 in visceral fat and red fiber-type muscle are differently regulated by circulating lipids and that selective insulin resistance seems to favor, at least in part, a prevention of fat accumulation in tissues not primarily destined for fat storage, thus contributing to increased adiposity and the development of a prediabetic syndrome.
 ...
PMID:Preferential channeling of energy fuels toward fat rather than muscle during high free fatty acid availability in rats. 1124 80

Enlarged fat cells exhibit modified metabolic capacities, which could be involved in the metabolic complications of obesity at the whole body level. We show here that sterol regulatory element-binding protein 2 (SREBP-2) and its target genes are induced in the adipose tissue of several models of rodent obesity, suggesting cholesterol imbalance in enlarged adipocytes. Within a particular fat pad, larger adipocytes have reduced membrane cholesterol concentrations compared with smaller fat cells, demonstrating that altered cholesterol distribution is characteristic of adipocyte hypertrophy per se. We show that treatment with methyl-beta-cyclodextrin, which mimics the membrane cholesterol reduction of hypertrophied adipocytes, induces insulin resistance. We also produced cholesterol depletion by mevastatin treatment, which activates SREBP-2 and its target genes. The analysis of 40 adipocyte genes showed that the response to cholesterol depletion implicated genes involved in cholesterol traffic (caveolin 2, scavenger receptor BI, and ATP binding cassette 1 genes) but also adipocyte-derived secretion products (tumor necrosis factor alpha, angiotensinogen, and interleukin-6) and proteins involved in energy metabolism (fatty acid synthase, GLUT 4, and UCP3). These data demonstrate that altering cholesterol balance profoundly modifies adipocyte metabolism in a way resembling that seen in hypertrophied fat cells from obese rodents or humans. This is the first evidence that intracellular cholesterol might serve as a link between fat cell size and adipocyte metabolic activity.
 ...
PMID:Cholesterol, a cell size-dependent signal that regulates glucose metabolism and gene expression in adipocytes. 1127 95

Chronic stimulation of the beta3-adrenergic receptor (AR) in obese animals resulted in a reduced adiposity associated with an increased expression of thermogenic uncoupling protein (UCP)1 in adipose tissues. In this study, the mRNA expression of newly cloned UCP isoforms (UCP2 and UCP3) were examined in obese yellow KK and C57BL control mice. UCP2 mRNA was found in all tissues examined, with higher levels in adipose tissues and skeletal muscle of the obese mice. UCP3 mRNA was expressed in skeletal muscle, heart and brown adipose tissue similarly in the two mouse strains. Daily injection of a selective beta3-adrenergic agonist, CL316,243 (0.1 mg/kg), for 10 days resulted in a marked reduction of white fat pad weight and 1.8-4.8-fold increase in the mRNA levels of UCP2 and UCP3 in skeletal muscle of obese mice. No noticeable change in the UCP2 and 3 mRNA levels was found in brown and white adipose tissues. It was also found that CL316,243 injection produced a marked and sustained elevation of the plasma free fatty acid level. These results, together with our previous findings of the fatty acid-induced UCP expression in a myocyte cell line in vitro, suggest that the beta3-AR agonist-induced UCP expression in skeletal muscle may be mediated through the elevated plasma free fatty acids. It was also suggested that anti-obesity effect of beta3-AR agonists is attributable to increased thermogenesis not only by UCP1 but also by UCP2 and UCP3.
 ...
PMID:Beta 3-adrenergic agonist up-regulates uncoupling proteins 2 and 3 in skeletal muscle of the mouse. 1130 32

Obesity is the most common nutritional disorder in Western society. Uncoupling protein-2 (UCP2) is a recently identified member of the mitochondrial transporter superfamily that is expressed in many tissues, including adipose tissue. Like its close relatives UCP1 and UCP3, UCP2 uncouples proton entry in the mitochondrial matrix from ATP synthesis and is therefore a candidate gene for obesity. We show here that a common G/A polymorphism in the UCP2 promoter region is associated with enhanced adipose tissue mRNA expression in vivo and results in increased transcription of a reporter gene in the human adipocyte cell line PAZ-6. In analyzing 340 obese and 256 never-obese middle-aged subjects, we found a modest but significant reduction in obesity prevalence associated with the less-common allele. We confirmed this association in a population-based sample of 791 middle-aged subjects from the same geographic area. Despite its modest effect, but because of its high frequency (approximately 63%), the more-common risk allele conferred a relatively large population-attributable risk accounting for 15% of the obesity in the population studied.
 ...
PMID:A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. 1138 Dec 68

Obesity is now regarded as major public health problem worldwide. Research into this condition has been increasingly focussed on elucidating the cellular and molecular mechanisms regulating mammalian energy intake and expenditure. It is widely acknowledged that the brown adipose tissue (BAT) mitochondrial uncoupling protein (UCP1) plays a pivotal role in adaptive thermogenic responses. Two homologues of UCP1 (UCP2 and UCP3) have recently been identified and population-based genetic studies have linked them with basal metabolic rate, while in vitro studies report that both have proton transport activity and may thus be involved in regulation of energy homeostasis and hence obesity. However, evidence from genetically modified animal models indicates that UCP2 and UCP3 have no specific physiological thermogenic function in vivo, though they may still be useful therapeutic targets for obesity. Furthermore, their role in modulating levels of reactive oxygen species and glucose homeostasis is also being investigated.
 ...
PMID:Mitochondrial uncoupling proteins (UCPs) and obesity. 1138 27


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>