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 synthetic compound NO-1886 (ibrolipim, [4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester, CAS 133208-93-2) is a lipoprotein lipase (LPL)-promoting agent that decreases plasma triglycerides, increases high-density lipoprotein cholesterol levels, and prevents fat accumulation in high fat-fed rats. However, the effect of NO-1886 on body weight, fat accumulation, and energy expenditure in ovariectomized (OVX) rats is not clear. The primary aim of this study was to ascertain whether NO-1886 ameliorated obesity in OVX rats and to examine the effects on fatty acid oxidation-related enzymes. NO-1886 decreased accumulation of visceral fat and suppressed the increase in body weight resulting from the ovariectomy. NO-1886 decreased the respiratory quotient and increased expression of the fatty acid translocase messenger RNA (mRNA) in the liver, soleus muscle, and mesenteric fat. NO-1886 also increased the expression of fatty acid-binding protein mRNA in the liver and soleus muscle and the expression of the uncoupling protein 3 (UCP3) mRNA in the heart, soleus muscle, and mesenteric fat, but not in the brown adipose tissue. Furthermore, NO-1886 did not affect UCP1 and UCP2 in brown adipose tissue. Therefore, amelioration of obesity by NO-1886 in OVX rats is possibly because of an the increased expression of fatty acid oxidation-related enzymes and UCP3, both of which are related to fatty acid transfer and fat use. Our study indicates that the LPL-promoting agent NO-1886 may be potentially beneficial in the treatment of obesity and obesity-linked health problems in postmenopausal women.
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PMID:NO-1886 (ibrolipim), a lipoprotein lipase-promoting agent, accelerates the expression of UCP3 messenger RNA and ameliorates obesity in ovariectomized rats. 1642 20

The leaf of Nelumbo nucifera Gaertn. (family Nymphaeaceae) has been used for summer heat syndrome as home remedy in Japan and China, and it has recently been used to treat obesity in China. So we investigate the pharmacological mechanism of the anti-obesity effect of Nelumbo nucifera leaves extract (NNE). We examined the effect of NNE on digestive enzyme activity, lipid metabolism and theromogenesis and evaluated the effects of anti-obesity using high-fat diet-induced obesity in mice that were treated with NNE for 5 weeks. NNE caused a concentration-dependent inhibition of the activities of alpha-amylase and lipase, and up-regulated lipid metabolism and expression of UCP3 mRNA in C2C12 myotubes. NNE prevented the increase in body weight, parametrial adipose tissue weight and liver triacylglycerol levels in mice with obesity induced by a high-fat diet. UCP3 mRNA expression in skeletal muscle tended to be higher, when mice were administrated by NNE and were exercised. Therefore, NNE impaired digestion, inhibited absorption of lipids and carbohydrates, accelerated lipid metabolism and up-regulated energy expenditure. Consequently, NNE is beneficial for the suppression of obesity.
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PMID:Anti-obesity effect of Nelumbo nucifera leaves extract in mice and rats. 1649 25

Responses to energy restriction tend to vary within the population because of genetic differences. In this study, we have genotyped 6 uncoupling protein 3 (UCP-3) polymorphisms (-55C/T, Int2-143G/C, Tyr99Tyr, Int3-47G/A, Int4-498C/T, and Tyr210Tyr) among 214 overweight Korean female subjects recruited from an obesity clinic. Three major haplotypes, identified with frequencies in excess of 0.04, were constructed from 6 single nucleotide polymorphisms. Association studies were then undertaken, involving the measurement of anthropometric characteristics and body composition both before and after 1 month of a energy-restriction regimen. At baseline, haplotype 1 (ht1) [CGTACC] was associated with elevated anthropometric characteristics, including body weight, waist-hip ratio, and body mass index, as well as body components, including body fat mass and body fat-free mass. After the completion of the 1-month weight control program, which involved a very low-energy (2900 kJ/d) diet, we analyzed the outcomes according to the UCP-3 genetic polymorphisms. Among the 3 principal haplotypes, ht1 [CGTACC] was significantly associated with an increased reduction in body weight, in the codominant (P=.022), dominant (P=.016), and recessive (P=.041) models. Body mass index reduction was associated with the ht1 haplotype in a similar fashion. Among the body components, changes in body fat mass were significantly associated with ht1 [CGTACC] (P=.028), but changes in body fat-free mass were not significantly associated with the UCP-3 polymorphism.
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PMID:The effects of uncoupling protein 3 haplotypes on obesity phenotypes and very low-energy diet-induced changes among overweight Korean female subjects. 1663 32

The impact of the UCP2 -866G>A and UCP3 -55C>T variants on prospective risk of type 2 diabetes was examined over 15 years in 2,936 healthy middle-aged men (mean age 56 years). Conversion to diabetes (n = 169) was associated with higher BMI, blood pressure, cholesterol, triglycerides and C-reactive protein. The hazard ratio (HR) for diabetes of a BMI >30 kg/m(2) was 3.96 (95% CI 2.87-5.47). Homozygosity for the UCP2A or UCP3T alleles accelerated the onset of diabetes, with significant differences in risk of diabetes at 10 years (HR [95% CI] UCP2AA vs. GA+GG 1.94 [1.18-3.19], P = 0.009; UCP3TT vs. CC+ CT 2.06 [1.06-3.99], P = 0.03) but less so at 15 years (UCP2AA 1.42 [0.92-2.19], P = 0.1; UCP3TT 1.57 [0.87-2.04], P = 0.13). Men who were homozygous for both UCP2AA and UCP3TT (1.5% of men) had a risk for diabetes at 10 years of 4.20 (1.70-10.37), P = 0.002. These genotype effects were additive with obesity, and men with a BMI >30 kg/m(2) and this genotype combination had a 10-year risk of diabetes of 19.23 [5.63-63.69], P < 0.0001. Functional promoter variants UCP2 and UCP3 increase the prospective risk of diabetes. Although the mechanism of the UCP2 effect is likely to be caused by increased expression in the pancreas and subsequent reduced insulin secretion, the mechanism of the UCP3 effect is currently unknown. Both effects are exacerbated by obesity.
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PMID:Variation in the UCP2-UCP3 gene cluster predicts the development of type 2 diabetes in healthy middle-aged men. 1664 12

There has been intense interest in defining the functions of UCP2 and UCP3 during the nine years since the cloning of these UCP1 homologues. Current data suggest that both UCP2 and UCP3 proteins share some features with UCP1, such as the ability to reduce mitochondrial membrane potential, but they also have distinctly different physiological roles. Human genetic studies consistently demonstrate the effect of UCP2 alleles on type-2 diabetes. Less clear is whether UCP2 alleles influence body weight or body mass index (BMI) with many studies showing a positive effect while others do not. There is strong evidence that both UCP2 and UCP3 protect against mitochondrial oxidative damage by reducing the production of reactive oxygen species. The evidence that UCP2 protein is a negative regulator of insulin secretion by pancreatic beta-cells is also strong: increased UCP2 decreases glucose stimulated insulin secretion ultimately leading to beta-cell dysfunction. UCP2 is also neuroprotective, reducing oxidative stress in neurons. UCP3 may also transport fatty acids out of mitochondria thereby protecting the mitochondria from fatty acid anions or peroxides. Current data suggest that UCP2 plays a role in the metabolic syndrome through down-regulation of insulin secretion and development of type-2 diabetes. However, UCP2 may protect against atherosclerosis through reduction of oxidative stress and both UCP2 and UCP3 may protect against obesity. Thus, these UCP1 homologues may both contribute to and protect from the markers of the metabolic syndrome.
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PMID:Uncoupling proteins, dietary fat and the metabolic syndrome. 1696 50

Chronic topical treatment of rats with a new RARgamma-selective retinoid, ER36009, resulted in a significant reduction of epididymal white adipose tissue and a significant increase of interscapular brown adipose tissue without affecting food intake. ER36009 markedly decreased PPARgamma, 11beta-HSD1, and Bcl-2 mRNA levels, and increased Bax mRNA in white adipose tissue, while it upregulated UCP1 and UCP3 mRNAs in brown adipose tissue and UCP3 mRNA in gastrocnemial muscle. These results suggest that ER36009 has multiple effects on adipose tissue biology and the energy balance. Topically applied ER36009 may have potential for the treatment of obesity.
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PMID:Topical ER36009, a RARgamma-selective retinoid, decreases abdominal white adipose tissue and elicits changes in expression of genes related to adiposity and thermogenesis. 1718 99

Disturbances in energy homeostasis can result in obesity and other metabolic diseases. Here we report a metabolic pathway present in normal human skeletal muscle myoblasts that is activated by the small polyphenolic molecule kaempferol (KPF). Treatment with KPF leads to an approximately 30% increase in skeletal myocyte oxygen consumption. The mechanism involves a several-fold increase in cyclic AMP (cAMP) generation and protein kinase A activation, and the effect of KPF can be mimicked via treatment with dibutyryl cAMP. Microarray and real-time PCR studies identified a set of metabolically relevant genes influenced by KPF including peroxisome proliferator-activated receptor gamma coactivator-1alpha, carnitine palmitoyl transferase-1, mitochondrial transcription factor 1, citrate synthase, and uncoupling protein-3, although KPF itself is not a direct mitochondrial uncoupler. The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF; furthermore, the activity half-life for D2 is dramatically and selectively increased as well. The net effect is an approximately 10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of approximately 2.6-fold in the rate of T3 production, which persists even 24 h after KPF has been removed from the system. The effects of KPF on D2 are independent of sirtuin activation and only weakly reproduced by other small polyphenolic molecules such as quercetin and fisetin. These data document a novel mechanism by which a xenobiotic-activated pathway can regulate metabolically important genes as well as thyroid hormone activation and thus may influence metabolic control in humans.
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PMID:The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. 1732 47

A high dietary fat intake and low physical activity characterize the current Western lifestyle. Dietary fatty acids do not stimulate their own oxidation and a surplus of fat is stored in white adipose tissue, liver, heart and muscle. In these organs intracellular lipids serve as a rapidly-available energy source during, for example, physical activity. However, under conditions of elevated plasma fatty acid levels and high dietary fat intake, conditions implicated in the development of modern diseases such as obesity and type 2 diabetes mellitus, fat accumulation in liver and muscle (intramyocellular lipids; IMCL) is associated with the development of insulin resistance. Recent data suggest that IMCL are specifically harmful when combined with reduced mitochondrial function, both conditions that characterize type 2 diabetes. In the (pre)diabetic state reduced expression of the transcription factor PPARgamma co-activator-1alpha (PGC-1alpha), which is involved in mitochondrial biogenesis, has been suggested to underlie the reduced mitochondrial function. Importantly, the reduction in PGC-1alpha may be a result of low physical activity, consumption of high-fat diets and high plasma fatty acid levels. Mitochondrial function can also be impaired as a result of enhanced mitochondrial damage by reactive oxygen species. Fatty acids in the vicinity of mitochondria are particularly prone to lipid peroxidation. In turn, lipid peroxides can induce oxidative damage to mitochondrial RNA, DNA and proteins. The mitochondrial protein uncoupling protein 3, which is induced under high-fat conditions, may serve to protect mitochondria against lipid-induced oxidative damage, but is reduced in the prediabetic state. Thus, muscular lipotoxicity may impair mitochondrial function and may be central to insulin resistance and type 2 diabetes mellitus.
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PMID:High-fat diet, muscular lipotoxicity and insulin resistance. 1734 70

We tested the hypothesis of a lower respiratory capacity per mitochondrion in skeletal muscle of type 2 diabetic patients compared with obese subjects. Muscle biopsies obtained from 10 obese type 2 diabetic and 8 obese nondiabetic male subjects were used for assessment of 3-hydroxy-Acyl-CoA-dehydrogenase (HAD) and citrate synthase activity, uncoupling protein (UCP)3 content, oxidative stress measured as 4-hydroxy-2-nonenal (HNE), fiber type distribution, and respiration in isolated mitochondria. Respiration was normalized to citrate synthase activity (mitochondrial content) in isolated mitochondria. Maximal ADP-stimulated respiration (state 3) with pyruvate plus malate and respiration through the electron transport chain (ETC) were reduced in type 2 diabetic patients, and the proportion of type 2X fibers were higher in type 2 diabetic patients compared with obese subjects (all P < 0.05). There were no differences in respiration with palmitoyl-l-carnitine plus malate, citrate synthase activity, HAD activity, UCP3 content, or oxidative stress measured as HNE between the groups. In the whole group, state 3 respiration with pyruvate plus malate and respiration through ETC were negatively associated with A1C, and the proportion of type 2X fibers correlated with markers of insulin resistance (P < 0.05). In conclusion, we provide evidence for a functional impairment in mitochondrial respiration and increased amount of type 2X fibers in muscle of type 2 diabetic patients. These alterations may contribute to the development of type 2 diabetes in humans with obesity.
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PMID:Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. 1735 Nov 50

Leucine, as an essential amino acid and activator of mTOR (mammalian target of rapamycin), promotes protein synthesis and suppresses protein catabolism. However, the effect of leucine on overall glucose and energy metabolism remains unclear, and whether leucine has beneficial effects as a long-term dietary supplement has not been examined. In the present study, we doubled dietary leucine intake via leucine-containing drinking water in mice with free excess to either a rodent chow or a high-fat diet (HFD). While it produced no major metabolic effects in chow-fed mice, increasing leucine intake resulted in up to 32% reduction of weight gain (P < 0.05) and a 25% decrease in adiposity (P < 0.01) in HFD-fed mice. The reduction of adiposity resulted from increased resting energy expenditure associated with increased expression of uncoupling protein 3 in brown and white adipose tissues and in skeletal muscle, while food intake was not decreased. Increasing leucine intake also prevented HFD-induced hyperglycemia, which was associated with improved insulin sensitivity, decreased plasma concentrations of glucagon and glucogenic amino acids, and downregulation of hepatic glucose-6-phosphatase. Additionally, plasma levels of total and LDL cholesterol were decreased by 27% (P < 0.001) and 53% (P < 0.001), respectively, in leucine supplemented HFD-fed mice compared with the control mice fed the same diet. The reduction in cholesterol levels was largely independent of leucine-induced changes in adiposity. In conclusion, increases in dietary leucine intake substantially decrease diet-induced obesity, hyperglycemia, and hypercholesterolemia in mice with ad libitum consumption of HFD likely via multiple mechanisms.
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PMID:Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. 1736 Sep 78


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