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)

Obese Zucker rats were dosed orally for one week with fenofibrate (100 mg/kg). Liver weights of treated rats as expressed as percent of body weight were slightly increased, while protein, DNA and lipid contents were unaffected per g of liver or increased when expressed in whole liver. Compared with the control animals, activities of fatty acid oxidase, of the peroxisomal fatty acid-oxidizing system and of catalase were markedly increased by fenofibrate both per g of liver and per total liver, while urate oxidase activity was unchanged when expressed per g of liver. The activity of monoamine oxidase and that of cytochrome c oxidase used as marker enzymes for mitochondria were increased only when expressed per total liver. However, fenofibrate treatment induced a pronounced increase in the activities of mitochondrial palmitoyl-CoA dehydrogenase and carnitine acyltransferases, particularly carnitine acetyltransferase. Fenofibrate also caused a significant increase of carnitine content in liver and hepatic mitochondria. The greatest observed increases were in free carnitine and in the rate of carnitine-dependent oleate oxidation, which might be favoured in vivo by a lesser sensitivity of CPT-I to a malonyl-CoA inhibitory effect. The present results suggest that fenofibrate treatment induces increased hepatic mitochondrial beta-oxidation in obese Zucker rats.
 ...
PMID:Effects of fenofibrate treatment on fatty acid oxidation in liver mitochondria of obese Zucker rats. 366 37

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.
 ...
PMID:Up-regulation of liver uncoupling protein-2 mRNA by either fish oil feeding or fibrate administration in mice. 1020 78

Fenofibrate is a member of the fibrate class of hypolipidemic agents used clinically to treat hypertriglyceridemia and mixed hyperlipidemia. The fibrates were developed primarily on the basis of their cholesterol and triglyceride lowering in rodents. Fibrates have historically been ineffective at lowering triglycerides in experimentally-induced dyslipidemia in nonhuman primate models. The spontaneously obese rhesus monkey is a well-recognized animal model for the study of human obesity and type 2 diabetes, and many of these monkeys exhibit naturally occurring lipid abnormalities, including elevated triglycerides and low HDL cholesterol (HDL-C), similar to patients with type 2 diabetes. To explore whether the obese rhesus model was predictive of the lipid lowering effects of fibrates, we evaluated fenofibrate in six hypertriglyceridemic, hyperinsulinemic, nondiabetic animals in a 20-week, dose-escalating study. The study consisted of a 4-week baseline period, two treatment periods of 10 mg/kg twice daily (b.i.d) for 4 weeks and 30 mg/kg b.i.d. for 8 weeks, and a 4-week washout period. Fenofibrate (30 mg/kg b.i.d) decreased serum triglycerides 55% and LDL-C 27%, whereas HDL-C increased 35%. Apolipoproteins B-100 and C-III levels were also reduced 70% and 29%, respectively. Food intake, body weight, and plasma glucose were not affected throughout the study. Interestingly, plasma insulin levels decreased 40% during the 30 mg/kg treatment period, suggesting improvement in insulin sensitivity. These results support the use of obese rhesus monkey as an excellent animal model for studying the effects of novel hypolipidemic agents, particularly agents that impact serum triglycerides and HDL-C.
 ...
PMID:Effects of fenofibrate on lipid parameters in obese rhesus monkeys. 1159 Feb 9

To determine whether the PPARalpha agonist fenofibrate regulates obesity and lipid metabolism with sexual dimorphism, we examined the effects of fenofibrate on body weight, white adipose tissue (WAT) mass, circulating lipids, and the expression of PPARalpha target genes in both sexes of high fat diet-fed C57BL/6J mice. Both sexes of mice fed a high-fat diet for 14 weeks exhibited increases in body weight, visceral WAT mass, as well as serum triglycerides and cholesterol, although these effects were more pronounced among males. Feeding a high fat diet supplemented with fenofibrate (0.05% w/w) reduced all of these effects significantly in males except serum cholesterol level. Females on a fenofibrate-enriched high fat diet had reduced serum triglyceride levels, albeit to a smaller extent compared to males, but did not exhibit decreases in body weight, WAT mass, and serum cholesterol. Fenofibrate treatment resulted in hepatic induction of PPARalpha target genes encoding enzymes for fatty acid beta-oxidation, the magnitudes of which were much higher in males compared to females, as evidenced by results for acyl-CoA oxidase, a first enzyme of the beta-oxidation system. These results suggest that observed sexually dimorphic effects on body weight, WAT mass and serum lipids by fenofibrate may involve sexually related elements in the differential activation of PPARalpha.
 ...
PMID:Fenofibrate regulates obesity and lipid metabolism with sexual dimorphism. 1252 91

The adipocyte-derived cytokine, resistin, has been proposed as the link between obesity and type 2 diabetes mellitus in murine models. In humans, resistin is identical to FIZZ3 (found in inflammatory zone 3), which belongs to a family of proteins that appears to be involved in inflammatory processes. To study the mechanisms by which fibrates improve glucose homeostasis, we determined resistin mRNA levels by using relative quantitative reverse-transcriptase-polymerase chain reaction (RT-PCR) in omental white adipose tissue samples obtained from patients treated with placebo or fenofibrate (200 mg/d) for 8 weeks before elective cholecystectomy. Fenofibrate treatment reduced total plasma cholesterol and low-density lipoprotein (LDL)-cholesterol levels by 24% and 35%, respectively. Compared with placebo values, a 2.4-fold induction in resistin mRNA levels was observed in white adipose tissue of fenofibrate-treated patients, whereas no changes were observed in the mRNA levels of the well-known perosixome proliferator-activated receptor (PPAR) target genes CD36, acyl-CoA oxidase, and carnitine palmitoyltransferase. These findings indicate that resistin changes were not related to PPAR activation by fenofibrate. Interestingly, resistin mRNA levels showed a negative correlation with plasma cholesterol levels (r2 =.53, P =.039, n = 8), but not with triglyceride levels (r2 =.02, P =.73, n = 8). These results suggest that cholesterol regulates resistin expression in human white adipose tissue.
 ...
PMID:Reductions in plasma cholesterol levels after fenofibrate treatment are negatively correlated with resistin expression in human adipose tissue. 1264 75

Fenofibrate, a peroxisome proliferated activated receptor alpha (PPARalpha) agonist, has been shown to decrease plasma triglyceride (TG) and increase plasma high-density lipoprotein (HDL) cholesterol levels despite a large interindividual variation in the response. Fenofibrate-activated PPARalpha binds to a DNA sequence element termed PPAR response element (PPRE) present in regulatory regions of target genes. A PPRE has been identified in the proximal 5' flanking region of the gene encoding the liver fatty acid binding protein (LFABP). LFABP is a small cytosolic protein of 14 kDa present in the liver and the intestine and is a member of the superfamily of the fatty acid binding proteins (FABPs). FABPs play a role in the solubilization of long-chain fatty acids (LCFAs) and their CoA-ester to various intracellular organelles. FABPs serves as intracellular acceptors of LCFAs, and they may also have an impact in ligand-dependent transactivation of PPARs in trafficking LCFAs to the nucleus. Since PPARs are known to regulate the transcription of many genes involved in lipid metabolism, the importance of LFABP in fatty acid uptake has to be considered. The aim of this study was to verify whether genetic variations in the LFABP gene may impact on plasma lipoprotein/lipid levels in the fasting state as well as on the response to a lipid-lowering therapy with fenofibrate on plasma lipids and obesity variables. We also wanted to verify whether the presence of the PPARalpha L162V mutation interacts with genetic variants in LFABP gene. To achieve this goal, we first determined the genomic structure of the human LFABP gene and then designed intronic primers to sequence the coding regions, all exon-intron splicing boundaries, and the promoter region of the gene in 24 patients showing divergent plasma lipoprotein/lipid response to fenofibrate. Sequence analysis revealed the presence of a T94A missense mutation in exon 3. Interspecies comparison revealed that threonine 94 is conserved among species. We subsequently screened another sample of 130 French Canadian subjects treated with fenofibrate for the presence of the LFABP T94A mutation. Carriers of the A94 allele were at increased risk to exhibit plasma TG levels above 2.00 mmol/l after treatment with fenofibrate [2.75 (1.03-7.34); OR 95% confidence interval (CI)]. In addition, carriers of the A94 allele were characterized by higher baseline plasma-free fatty acid levels (FFA) ( p=0.01) and by a lower body mass index (BMI) ( p=0.05) and waist circumference ( p=0.005) than T94 homozygotes. Moreover, PPARalpha L162V and LFABP T94A showed to have a synergistic effect on BMI ( p interaction = 0.03). These results suggest that the LFABP T94A missense mutation could influence obesity indices as well as the risk to exhibit residual hypertriglyceridmia following a lipid-lowering therapy with fenofibrate.
 ...
PMID:Effect of liver fatty acid binding protein (FABP) T94A missense mutation on plasma lipoprotein responsiveness to treatment with fenofibrate. 1524 72

Our previous study suggested that fenofibrate affects obesity and lipid metabolism in a sexually dimorphic manner in part through the differential activation of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) in male and female C57BL/6J mice. To determine whether fenofibrate reduces body weight gain and adiposity in female sham-operated (Sham) and ovariectomized (OVX) C57BL/6J mice, the effects of fenofibrate on not only body weight, white adipose tissue (WAT) mass, and food intake, but also the expression of both leptin and PPARalpha target genes were measured. Compared to their respective low-fat diet-fed controls, both Sham and OVX mice exhibited increases in body weight and WAT mass when fed a high-fat diet. Fenofibrate treatment decreased body weight gain and WAT mass in OVX, but not in Sham mice. Furthermore, fenofibrate increased the mRNA levels of PPARalpha target genes encoding peroxisomal enzymes involved in fatty acid beta-oxidation, and reduced apolipoprotein C-III (apo C-III) mRNA, all of which were expressed at higher levels in OVX compared to Sham mice. However, leptin mRNA levels were found to positively correlate with WAT mass, and food intake was not changed in either OVX or Sham mice following fenofibrate treatment. These results suggest that fenofibrate differentially regulates body weight and adiposity due in part to differences in PPARalpha activation, but not to differences in leptin production, between female OVX and Sham mice.
 ...
PMID:Effects of fenofibrate on high-fat diet-induced body weight gain and adiposity in female C57BL/6J mice. 1537 83

In humans, dietary-induced obesity markedly increases plasma lipid profile and impairs vascular function leading to increased incidence of cardiovascular events. We have recently reported that chronic withdrawal of obesity-inducing diet attenuates obesity and completely corrects endothelial function. The aim of this study was to investigate whether fenofibrate-induced decrease in adiposity would also correct vascular function in the presence of obesity-inducing diet. Wistar rats were fed with either standard laboratory chow (lean, n = 9) or given a highly palatable diet (diet-fed, n = 18) for 15 weeks. After 7 weeks, half of the diet-fed group was treated with fenofibrate (fenofibrate-treated, n = 9) for 8 weeks before being sacrificed. Untreated diet-fed (n = 9) rats had significantly higher body weight, total fat mass (by up to two-fold, p < 0.001 for both), and raised fasting plasma levels of insulin, leptin and triglycerides (up to 110%; p < 0.001), but not glucose or nonesterified fatty acids (NEFA) than both lean control and fenofibrate-treated groups. Resistance mesenteric arteries responses to KCl- and noradrenaline-induced vasoconstriction were similar in all three groups. However, compared with lean controls, endothelium-dependent vasorelaxation responses were shifted to the right in both untreated and fenofibrate-treated diet-fed groups. Fenofibrate treatment improved endothelium-dependent vasorelaxation at only high carbamycholine concentrations (10 microM). There were no differences in endothelium-independent vasorelaxation between the three groups. These results indicate that, in the presence of obesity-inducing diet, fenofibrate markedly reverses obesity and corrects insulin resistance and lipid profile, but it only has a limited beneficial effect on vascular function. Therefore, it seems that diet component rather than obesity per se plays a key role in the genesis of vascular abnormalities.
 ...
PMID:Fenofibrate lowers adiposity and corrects metabolic abnormalities, but only partially restores endothelial function in dietary obese rats. 1553 Sep 4

High-fat diets (HFDs) promote hyperphagia and adiposity in animals and human beings. To test the hypothesis that limitations on fat oxidation underlie this propensity for diet-induced obesity, rats were treated with fenofibrate, which enhances fat oxidation mainly in liver by inducing expression of enzymes and proliferation of organelles involved in fatty acid oxidation. Male Sprague-Dawley rats were fed a HFD (42% fat calorie) for 2 weeks. Rats ranked in the top and bottom thirds for weight gain during this feeding period were designated as obesity prone (OP) and obesity resistant (OR), respectively. Fenofibrate was added to the HFD (0.025% wt/wt) for half of the OP and OR rats. During the next 10 days, fenofibrate treatment significantly (P<.05) reduced food intake, weight gain, feed efficiency, and adiposity in OP rats to levels seen in control OR rats, but had no such effects in OR rats. Fenofibrate treatment increased whole-body fatty acid oxidation, and in liver, the expression of carnitine palmitoyl transferase I only in OP rats, but enhanced expression of acyl-CoA oxidase in both OP and OR rats. Restricting food intake of OP rats to levels seen in rats given fenofibrate similarly reduced weight gain but had little effect on weight of fat pads. Treatment with the daily dosage of fenofibrate given as a bolus did not produce a conditioned flavor aversion. These results suggest that enhancement of mitochondrial fatty acid oxidation in liver may be an effective phenotype-based treatment strategy for dietary obesity.
 ...
PMID:Phenotype-based treatment of dietary obesity: differential effects of fenofibrate in obesity-prone and obesity-resistant rats. 1579 46

Fenofibrate, a selective (1)PPAR-alpha activator, is prescribed to treat human dyslipidemia. The aim of this study was to delineate the mechanism of fenofibrate-mediated reductions in adiposity, improvements in insulin sensitivity, and lowering of triglycerides (TG) and free fatty acids (FFA) and to investigate if these favorable changes are related to the inhibition of lipid deposition in the aorta. To test this hypothesis we used male LDLr deficient mice that exhibit the clinical features of metabolic syndrome X when fed a high fat high cholesterol (HF) diet. LDLr deficient mice fed HF diet and simultaneously treated with fenofibrate (100 mg/kg body weight) prevented development of obesity, lowered serum triglycerides and cholesterol, improved insulin sensitivity, and prevented accumulation of lipids in the aorta. Lowering of circulating lipids occurred via down-regulation of lipogenic genes, including fatty acid synthase, acetyl CoA carboxylase and diacyl glycerol acyl transferase-2, concomitant with decreased liver TG and cholesterol, and TG output rate. Fenofibrate also suppressed liver apoCIII mRNA levels and markedly increased lipoprotein lipase mRNA levels, known to enhance serum TG catabolism. In addition, fenofibrate profoundly reduced epididymal fat and mesenteric fat mass to the levels seen in lean mice. The reductions in body weight were associated with elevation of hepatic uncoupling protein 2 (UCP2) mRNA, a concomitant increase in the ketone body formation, and improved insulin sensitivity associated with tumor necrosis factor-alpha reductions and phosphoenol pyruvate carboxykinase down-regulation. These results demonstrate that fenofibrate improves lipid abnormalities partly via inhibition of TG production and partly via clearance of TG-rich apoB particles by elevating LPL and reduced apoCIII. The prevention of obesity development occurred via energy expenditure. Fenofibrate-mediated hypolipidemic effects together with improved insulin sensitivity and loss of adiposity led to the reductions in the aortic lipid deposition by inhibiting early stages of atherosclerosis possibly via vascular cell adhesion molecule-1 (VCAM-1) modulation. These results suggest that potent PPAR-alpha activators may be useful in the treatment of syndrome X.
 ...
PMID:Peroxisome proliferator-activated receptor-alpha selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. 1647 80


1 2 3 Next >>