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)

In this study, to determine if age associated changes in fat metabolism in skeletal muscle and liver were related with sympathetic activity, we measured sympathetic activity and palmitate oxidation rate, carnitine palmitoyltransferase-1 (CPT-1) activity, and triglyceride concentration in skeletal muscle and liver of rats at 8, 30 and 60 weeks of age. Body weight, intra-abdominal percent of fat mass, and plasma level of insulin, leptin, and triglyceride were all significantly increased with age. Tissue triglyceride concentration was increased with age in liver and skeletal muscle. The palmitate oxidation rate in liver and skeletal muscle was reduced with age in rats and inversely correlated with tissue triglyceride concentration. CPT-1 activity was not altered with age. Plasma catecholamine concentration and sympathetic activity, as measured by spectral analysis of heart rate variability, were increased with age. Plasma norepinephrine or epinephrine and tissue triglyceride had a positive correlation in liver and skeletal muscle. Plasma norepinephrine or epinephrine to tissue triglyceride ratio was similar according to age. In summary, in spite of increased sympathetic activity with age, the tissue triglyceride concentration was increased. Increased sympathetic activity may be the compensatory response and the reduced capacity of fatty acid oxidation is a main cause of obesity.
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PMID:Age-associated changes in fat metabolism in the rat and its relation to sympathetic activity. 1689 Sep 63

Topiramate (Topamax), primarily prescribed against epilepsy, was reported to reduce body weight and to ameliorate glycemic control in obese patients with diabetes. In rodent models of obesity and diabetes, topiramate treatment counteracts hyperglycemia and increases insulin levels upon glucose tolerance test. These observations suggest that topiramate might exert direct action on insulin secreting cells, in particular regarding obesity associated beta-cell dysfunction. In this study, INS-1E beta-cells were exposed for 3 days to the fatty acid oleate (0.4mM) and concomitantly treated with therapeutic concentrations of topiramate before measurements of insulin secretion and metabolic parameters. In healthy cells, topiramate had no acute or chronic effects on insulin release. Exposure of INS-1E cells to oleate for 3 days increased insulin release at basal 2.5mM glucose and blunted the response to stimulatory glucose concentration (15mM). Such lipotoxic effects were associated with impaired mitochondrial function, as evidenced by partial loss of resting mitochondrial membrane potential and reduced hyperpolarization in response to glucose. Oil-red-O staining and triglyceride measurements revealed lipid accumulation in oleate treated cells. Topiramate treatment counteracted oleate-induced lipid load and partially protected against mitochondrial membrane dysfunction. In particular, topiramate restored glucose stimulated insulin secretion, essentially by maintaining low insulin release at basal glucose. Topiramate increased expression of the nutrient sensor PPARalpha and of the mitochondrial fatty acid carrier CPT-1, correlating with enhancement of beta-oxidation rate. The data demonstrate that a drug originally used as mood stabilizer exerts a direct action on beta-cells, protecting against lipid-induced dysfunction.
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PMID:The antiepileptic drug topiramate preserves metabolism-secretion coupling in insulin secreting cells chronically exposed to the fatty acid oleate. 1693 63

A potential role for fatty acid metabolism in the regulation of energy balance in the brain or in the periphery has been considered only recently. Fatty acid synthase (FAS) catalyzes the synthesis of long-chain fatty acids, whereas the breakdown of fatty acids by beta-oxidation is regulated by carnitine palmitoyltransferase-1, the rate-limiting enzyme for the entry of fatty acids into the mitochondria for oxidation. While the question of the physiological role of fatty acid metabolism remains to be resolved, studies indicate that inhibition of FAS or stimulation of carnitine palmitoyltransferase-1 using cerulenin or synthetic FAS inhibitors reduces food intake and incurs profound and reversible weight loss. Several hypotheses regarding the mechanisms by which these small molecules mediate their effects have been entertained. Centrally, these compounds alter the expression of hypothalamic neuropeptides, generally reducing the expression of orexigenic peptides. Whether through central, peripheral, or combined central and peripheral mechanisms, these compounds also increase energy consumption to augment weight loss. In vitro and in vivo studies indicate that at least part of C75's effects is mediated by modulation of adenosine monophosphate-activated protein kinase, a member of an energy-sensing kinase family. These compounds, with chronic treatment, also alter gene expression peripherally to favor a state of enhanced energy consumption. Together, these effects raise the possibility that pharmacological alterations in fatty acid synthesis/degradation may serve as a target for obesity therapeutics.
Obesity (Silver Spring) 2006 Aug
PMID:Fatty acid metabolism, the central nervous system, and feeding. 1702 67

Obesity is under the influence of genetic and nutritional factors. The objective was to verify whether variants in the gene encoding the carnitine palmitoyltransferase I (CPT1), a key enzyme in beta-oxidation of fatty acids, are associated with obesity phenotypes, alone or in interaction with fat intake. Sequencing of CPT1 was performed in 40 overweight subjects and 4 controls. Genotypes were determined in 351 French-Canadians. Fat intake was evaluated by a food frequency questionnaire. We identified 14 genetic variations in CPT1A and 26 in CPT1B. Nine variants within CPT1B and one variant within CPT1A were selected for further analyses based on the minor allele frequency (>10%) or on potential functional impact. A significant association between obesity phenotypes (BMI, weight, and waist girth) and CPT1B c.282-18C > T and p.E531K variants was observed (p < 0.05) No other association was found with variants in CPT1A and CPT1B. When subjects were divided into six groups according to p.E531K genotypes and further on the basis of fat using the median value as a cutoff point (34.4% of energy), BMI, weight, and waist girth were higher in E531/K531 on a high-fat diet compared to E531/K531 subjects under a low-fat diet (p = 0.004, p = 0.006, p = 0.003, respectively). There was no difference among E531/E531 and K531/K531. Similar results were obtained with the CPT1A p.A275T variant as BMI and waist girth were higher in A275/A275 on a high fat compared to A275/A275 subjects on a low-fat diet. Among carriers of the T275 allele, obesity indices were not affected by fat intake (p = 0.05 and p = 0.008 for BMI and waist girth, respectively). Among variants within the CPT1B gene, 13 haplotypes were inferred and the two most frequent haplotypes, H7 (38.0%) and H5 (27.7%), were kept for diplotype analysis. These haplotypes were not associated with indices of obesity, but as observed with the CPT1B E531K variant fat intake modulated this association. In conclusion, this finding suggests that indices of obesity might be modulated by an interaction between CPT1 variants and fat intake.
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PMID:Variants within the muscle and liver isoforms of the carnitine palmitoyltransferase I (CPT1) gene interact with fat intake to modulate indices of obesity in French-Canadians. 1708 95

Obesity is an important contributor to the risk of developing insulin resistance, diabetes, and heart disease. Alterations in tissue levels of malonyl-CoA have the potential to impact on the severity of a number of these disorders. This review will focus on the emerging role of malonyl-CoA as a key "metabolic effector" of both obesity and cardiac fatty acid oxidation. In addition to being a substrate for fatty acid biosynthesis, malonyl-CoA is a potent inhibitor of mitochondrial carnitine palmitoyltransferase (CPT) 1, a key enzyme involved in mitochondrial fatty acid uptake. A decrease in myocardial malonyl-CoA levels and an increase in CPT1 activity contribute to an increase in cardiac fatty acid oxidation. An increase in malonyl-CoA degradation due to increased malonyl-CoA decarboxylase (MCD) activity may be one mechanism responsible for this decrease in malonyl-CoA. Another mechanism involves the inhibition of acetyl-CoA carboxylase (ACC) synthesis of malonyl-CoA, due to AMP-activated protein kinase (AMPK) phosphorylation of ACC. Recent studies have demonstrated a role of malonyl-CoA in the hypothalamus as a regulator of food intake. Increases in hypothalamic malonyl-CoA and inhibition of CPT1 are associated with a decrease in food intake in mice and rats, while a decrease in hypothalamic malonyl-CoA increases food intake and weight gain. The exact mechanism(s) responsible for these effects of malonyl-CoA are not clear, but have been proposed to be due to an increase in the levels of long chain acyl CoA, which occurs as a result of malonyl-CoA inhibition of CPT1. Both hypothalamic and cardiac studies have demonstrated that control of malonyl-CoA levels has an important impact on obesity and heart disease. Targeting enzymes that control malonyl-CoA levels may be an important therapeutic approach to treating heart disease and obesity.
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PMID:Role of malonyl-CoA in heart disease and the hypothalamic control of obesity. 1712 22

Dietary saturated fats have often been implicated in the promotion of obesity and related disorders. It has been shown recently that saturated fats act through the transcription factor SREBP-1c (sterol regulatory element-binding protein-1c) and its requisite coactivator, peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta), to exert their pro-lipogenic effects. We show here that a diet high in the saturated fat stearate induces lipogenic genes in wild-type mice, with the induction of the Scd1 (stearoyl-CoA desaturase-1) gene preceding that of other lipogenic genes. However, in Scd1-/- mice, stearate does not induce lipogenesis, and Srebp-1c and Pgc-1beta levels are markedly reduced. Instead, genes of fatty acid oxidation such as Cpt-1 (carnitine palmitoyltransferase-1) as well as Pgc-1alpha are induced. Mitochondrial fatty acid oxidation is increased, and white adipose tissue and hepatic glycogen stores are depleted in stearate-fed Scd1-/- mice. Furthermore, AMP-activated protein kinase is also induced by stearate feeding in Scd1-/- mice. These results indicate that the desaturation of saturated fats such as stearate by SCD is an essential step mediating their induction of lipogenesis. In the absence of SCD1, stearate promotes oxidation, leading to protection from saturated fat-induced obesity. SCD1 thus serves as a molecular switch in the promotion or prevention of lipid-induced disorders brought on by consumption of excess saturated fat.
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PMID:Stearoyl-CoA desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat. 1712 73

Soy products are mainly composed of proteins, phytochemicals such as isoflavones, soy lipids, and carbohydrates. It is unclear whether an individual component alone or a combined effect of multiple bioactive compounds contributes to the beneficial properties of soy. We investigated the effect of dietary genistein (the principal soy isoflavone) alone and combined with L-carnitine to evaluate possible synergistic effects on the intentionally induced prediabetic state characterized by insulin resistance and obesity in C57Bl/6J mice fed a high-fat diet (HD). In the HD-alone group, abdominal and back fat relative to total body weight were significantly higher compared with other groups including those fed normal diet (ND). Among the HD groups, final weight gains of the HD plus genistein (HD+G) and HD plus genistein plus L-carnitine (HD+G+C) groups were lower compared with that of the control (HD-alone). Especially in liver, the results showed that genistein with carnitine transcriptionally up-regulated expressions of acyl-coenzyme A synthetase (ACS) and carnitine palmitoyltransferase-I (CPT-I) by approximately 50% and 40%, respectively, compared with genistein alone. However, the up-regulation of CPT-I did not directly reflect the enzyme activity of CPT-I. On the other hand, the effects of genistein and genistein with carnitine on the expressions of ACS and CPT-I in muscle were not significant. Our study suggests that genistein with carnitine exerts anti-obesity effects, probably by modulating peroxisome proliferator-activated receptor-associated genes. However, further work is needed to elucidate the possible mechanisms by which genistein and carnitine intervene.
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PMID:Effect of genistein with carnitine administration on lipid parameters and obesity in C57Bl/6J mice fed a high-fat diet. 1720 30

We investigated the lipolytic effects of L-carnitine in 3T3-L1 adipocytes. L-carnitine at 10-S100 nM suppressed lipid accumulation. The release of glycerol and free fatty acid into the medium was significantly increased by 1.5- and 1.7- fold, respectively, by the addition of 100 nM L-carnitine compared with the control (P < .05). The mRNA levels of hormone-sensitive lipase, carnitine palmitoyltransferase I-a, and acyl-coenzyme A oxidase, all of which participate in lipid catabolism, were increased in the presence of 100 nM L-carnitine by 2.8-, 2.2-, and 1.6-fold, respectively (P < .05). However, the expression of peroxisome proliferator-activated receptor-gamma and adipose-specific fatty acid-binding protein, which are involved in adipogenesis, were down-regulated by L-carnitine in 3T3-L1 adipocytes (P < .05). These results suggest an anti-obesity action of L-carnitine. L-carnitine may modulate lipid metabolism by stimulation of lipolysis and beta-oxidation accompanied by corresponding changes in gene expression and suppression of adipogenic gene expression.
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PMID:L-carnitine stimulates lipolysis via induction of the lipolytic gene expression and suppression of the adipogenic gene expression in 3T3-L1 adipocytes. 1720 31

The aim of this study was to investigate the effects of a post-weaning isocaloric hyper-soybean oil diet on later obesity and explore the underlying mechanisms. In the present study, newborn male Wistar rats were weaned on d 24, divided into CON (control), HC and HSO groups. CON was assigned to AIN-93G diet (a hypercarbohydrate diet, for short HC diet) during the entire experiment. HC and HSO were fed with HC and isocaloric hyper-soybean oil (HSO) diet for 3 wk respectively, fed with HC diet for 2 wk successively, finally administrated high fat diet (HF) for 6 wk to induce obesity. On 3,5,11 wk, the body weight, body fat content, blood glucose, blood lipid, serum insulin and leptin levels and obesity-related gene (CPT-1, FAS, UCP2, UCP3) expression levels in rats were detected. It was shown that body weight, body fat content, blood glucose and blood lipid, serum insulin and leptin levels in HSO were down-regulated on 3 and 5 wk, therefore were significantly reduced on 11 wk vs. HC. The CPT-1, UCP2, UCP3 gene expressions were up-regulated but FAS were down-regulated persistently in HSO. The study indicated that an early isocaloric HSO diet may reduce later obesity risk and reduce blood lipid and glucose abnormalities in adulthood via persistently influencing insulin and leptin sensitivity and permanent regulation of obesity-related gene expressions.
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PMID:Post-weaning isocaloric hyper-soybean oil versus a hyper-carbohydrate diet reduces obesity in adult rats induced by a high-fat diet. 1739 34

The rising incidence of obesity, as a disorder of energy metabolism, has provoked a search for pharmacological agents that either increase energy expenditure or reduce food intake. The fatty acid oxidation pathway, and its rate-limiting enzyme carnitine palmitoyltransferase (CPT)-1 are potential targets for the treatment of obesity. The modulation of CPT-1 may simultaneously affect energy metabolism and food intake to aid in the management of obesity. Both the inhibition and enhancement of CPT-1 activity are currently under investigation as strategies for the treatment of obesity. In this review, key data on both sides of the 'CPT-1 activity balance' as they relate to obesity therapy are discussed.
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PMID:Modulation of carnitine palmitoyltransferase-1 for the treatment of obesity. 1745 81


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