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)

Carnitine palmitoyltransferase 1beta (CPT-1beta) is a key regulator of the beta oxidation of long-chain fatty acids in skeletal muscle and therefore a potential therapeutic target for diseases associated with defects in lipid metabolism such as obesity and type 2 diabetes. C75 [4-methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic acid] is an alpha-methylene-butyrolactone that has been characterized as both an inhibitor of fatty acid synthase and more recently, an activator of CPT-1 (Thupari et al., 2002). Using human CPT-1beta expressed in the yeast Pichia pastoris, we demonstrate that C75 can activate the skeletal muscle isoform of CPT-1 and overcome inactivation of the enzyme by malonyl CoA, an important physiological repressor of CPT-1, and the malonyl CoA mimetic Ro25-0187 [{5-[2-(naphthalen-2-yloxy)-ethoxy]-thiophen-2-yl}-oxo-acetic acid]. We also show that C75 can activate CPT-1 in intact hepatocytes to levels similar to those achieved with inhibition of acetyl-CoA carboxylase, the enzyme that produces malonyl CoA. Finally, we demonstrate that concentrations of C75 sufficient for activation of CPT-1 do not displace bound malonyl CoA. We conclude that CPT-1 is an activator of human CPT-1beta and other CPT-1 isoforms but that it does not activate CPT-1 through antagonism of malonyl CoA binding.
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PMID:C75 [4-methylene-2-octyl-5-oxo-tetrahydro-furan-3-carboxylic acid] activates carnitine palmitoyltransferase-1 in isolated mitochondria and intact cells without displacement of bound malonyl CoA. 1535 15

Over-the-counter dietary supplements to treat obesity appeal to many patients who desire a "magic bullet" for weight loss. Asking overweight patients about their use of weight-loss supplements and understanding the evidence for the efficacy, safety, and quality of these supplements are critical when counseling patients regarding weight loss. A schema for whether physicians should recommend, caution, or discourage use of a particular weight-loss supplement is presented in this article. More than 50 individual dietary supplements and more than 125 commercial combination products are available for weight loss. Currently, no weight-loss supplements meet criteria for recommended use. Although evidence of modest weight loss secondary to ephedra-caffeine ingestion exists, potentially serious adverse effects have led the U.S. Food and Drug Administration to ban the sale of these products. Chromium is a popular weight-loss supplement, but its efficacy and long-term safety are uncertain. Guar gum and chitosan appear to be ineffective; therefore, use of these products should be discouraged. Because of insufficient or conflicting evidence regarding the efficacy of conjugated linoleic acid, ginseng, glucomannan, green tea, hydroxycitric acid, L-carnitine, psyllium, pyruvate, and St. John's wort in weight loss, physicians should caution patients about the use of these supplements and closely monitor those who choose to use these products.
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PMID:Common dietary supplements for weight loss. 1555 92

Carnitine acyltransferases catalyze the exchange of acyl groups between carnitine and coenzyme A (CoA). These enzymes include carnitine acetyltransferase (CrAT), carnitine octanoyltransferase (CrOT), and carnitine palmitoyltransferases (CPTs). CPT-I and CPT-II are crucial for the beta-oxidation of long-chain fatty acids in the mitochondria by enabling their transport across the mitochondrial membrane. The activity of CPT-I is inhibited by malonyl-CoA, a crucial regulatory mechanism for fatty acid oxidation. Mutation or dysregulation of the CPT enzymes has been linked to many serious, even fatal human diseases, and these enzymes are promising targets for the development of therapeutic agents against type 2 diabetes and obesity. We have determined the crystal structures of murine CrAT, alone and in complex with its substrate carnitine or CoA. The structure contains two domains. Surprisingly, these two domains share the same backbone fold, which is also similar to that of chloramphenicol acetyltransferase and dihydrolipoyl transacetylase. The active site is located at the interface between the two domains, in a tunnel that extends through the center of the enzyme. Carnitine and CoA are bound in this tunnel, on opposite sides of the catalytic His343 residue. The structural information provides a molecular basis for understanding the catalysis by carnitine acyltransferases and for designing their inhibitors. In addition, our structural information suggests that the substrate carnitine may assist the catalysis by stabilizing the oxyanion in the reaction intermediate.
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PMID:Structure and function of carnitine acyltransferases. 1559 Oct

We have recently shown that elevated levels of free fatty acid (FFA) seen in insulin-resistant obese subjects are associated with endothelial dysfunction. L-carnitine, which is required for mitochondrial FFA transport/oxidation, has been reported to improve vascular function in subjects with diabetes and heart disease. Here, we tested the hypothesis that L-carnitine attenuates FFA-induced endothelial dysfunction. We studied leg blood flow (LBF) responses and leg vascular resistance (LVR) to graded intrafemoral artery infusions of the endothelium-dependent vasodilator, methacholine chloride (MCh). A group (n = 7) of normal lean subjects was studied under basal conditions (saline), after 2 h of FFA elevation (FFA), and then after 2 h of superimposing L-carnitine on FFA elevation. FFA elevation caused the maximal LBF increment in response to MCh to decrease from 0.388 +/- 0.08 to 0.212 +/- 0.071 L/min (P < 0.05). Similarly, FFA blunted the maximum decrease in LVR in response to MCh from -315 +/- 41 U to -105 +/- 46 U (P < 0.05). The superimposed L-carnitine restored the LBF increment in response to MCh to 0.488 +/- 0.088 L/min (P < 0.05 vs. FFA) and the maximum fall in LVR to -287 +/- 75 U (P < 0.05 vs. FFA), indicating that L-carnitine elevation may attenuate FFA-induced endothelial dysfunction. In conclusion, our data suggest that increasing L-carnitine levels may improve FFA-induced and obesity-associated endothelial dysfunction. This improved endothelial function may delay or prevent the development of excess cardiovascular disease.
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PMID:L-carnitine may attenuate free fatty acid-induced endothelial dysfunction. 1559 Oct 16

Increasing skeletal muscle carnitine content may alleviate the decline in muscle fat oxidation seen during intense exercise. Studies to date, however, have failed to increase muscle carnitine content, in healthy humans, by dietary or intravenous L-carnitine administration. We hypothesized that insulin could augment Na+-dependent skeletal muscle carnitine transport. On two randomized visits, eight healthy men underwent 5 h of intravenous L-carnitine infusion with serum insulin maintained at fasting (7.4+/-0.4 mIU*l(-1)) or physiologically high (149.2+/-6.9 mIU*l(-1)) concentrations. The combination of hypercarnitinemia (approximately 500 micromol*l(-1)) and hyperinsulinemia increased muscle total carnitine (TC) content from 22.0 +/- 0.9 to 24.7 +/- 1.4 mmol*(kg dm)(-1) (P<0.05) and was associated with a 2.3 +/- 0.3-fold increase in carnitine transporter protein (OCTN2) mRNA expression (P<0.05). Hypercarnitinemia in the presence of a fasting insulin concentration had no effect on either of these parameters. This study demonstrates that insulin can acutely increase muscle TC content in humans during hypercarnitinemia, which is associated with an increase in OCTN2 transcription. These novel findings may be of importance to the regulation of muscle fat oxidation during exercise, particularly in obesity and type 2 diabetes where it is known to be impaired.
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PMID:Insulin stimulates L-carnitine accumulation in human skeletal muscle. 1636 15

Carnitine acyltransferases catalyze the reversible exchange of acyl groups between coenzyme A (CoA) and carnitine. They have important roles in many cellular processes, especially the oxidation of long-chain fatty acids in the mitochondria for energy production, and are attractive targets for drug discovery against diabetes and obesity. To help define in molecular detail the catalytic mechanism of these enzymes, we report here the high resolution crystal structure of wild-type murine carnitine acetyltransferase (CrAT) in a ternary complex with its substrates acetyl-CoA and carnitine, and the structure of the S554A/M564G double mutant in a ternary complex with the substrates CoA and hexanoylcarnitine. Detailed analyses suggest that these structures may be good mimics for the Michaelis complexes for the forward and reverse reactions of the enzyme, representing the first time that such complexes of CrAT have been studied in molecular detail. The structural information provides significant new insights into the catalytic mechanism of CrAT and possibly carnitine acyltransferases in general.
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PMID:Crystal structures of murine carnitine acetyltransferase in ternary complexes with its substrates. 1687 Jun 16

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

Growing evidences indicate that proteases are implicated in adipogenesis and in the onset of obesity. We previously reported that the cysteine protease cathepsin K (ctsk) is overexpressed in the white adipose tissue (WAT) of obese individuals. We herein characterized the WAT and the metabolic phenotype of ctsk deficient animals (ctsk-/-). When the growth rate of ctsk-/- was compared to that of the wild type animals (WT), we could establish a time window (5-8 weeks of age) within which ctsk-/-display significantly lower body weight and WAT size as compared to WT. Such a difference was not observable in older mice. Upon treatment with high fat diet (HFD) for 12 weeks ctsk-/- gained significantly less weight than WT and showed reduced brown adipose tissue, liver mass and a lower percentage of body fat. Plasma triglycerides, cholesterol and leptin were significantly lower in HFD-fed-ctsk-/- as compared to HFD-fed WT animals. Adipocyte lipolysis rates were increased in both young and HFD-fed-ctsk-/-, as compared to WT. Carnitine palmitoyl transferase-1 activity, was higher in mitochondria isolated from the WAT of HFD treated ctsk-/- as compared to WT. Together, these data indicate that ctsk ablation in mice results in reduced body fat content under conditions requiring a rapid accumulation of fat stores. This observation could be partly explained by an increased release and/or utilization of FFA and by an augmented ratio of lipolysis/lipogenesis. These results also demonstrate that under a HFD, ctsk deficiency confers a partial resistance to the development of dyslipidemia.
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PMID:Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores. 1766 61

To develop an anti-obesity agent containing dietary components, we focused on the mechanisms that enhance both lipolysis and fatty acid oxidation. Caffeine and arginine (CA), a nonselective adenosine-receptor antagonist and an inducer of lipolytic hormone, respectively, were used to stimulate lipolysis. Soy isoflavones and L-carnitine (SL), stimulators of carnitine palmitoyl transferase 1A and a cofactor for beta-oxidation of fatty acids, respectively, were used to enhance fatty acid oxidation. Effects of a combination of CA and SL (CASL) on lipid metabolism were studied in vitro and in vivo. During 3T3-L1 differentiation, lipid accumulation was significantly lower in cells treated with CASL (50 micromol/L, 1 mmol/L, 1 micromol/L, and 1 mmol/L, respectively) compared with each alone. Lipolysis was also significantly greater in 3T3-L1 adipocytes treated with CASL (50 micromol/L, 1 mmol/L, 10 micromol/L and 0.5 mmol/L, respectively) compared with each alone. In addition, treatment with higher concentrations of CASL (2 mmol/L, 1 mmol/L, 10 micromol/L, and 1 mmol/L, respectively) significantly enhanced beta-oxidation in HepG2 cells. The effects of CASL-containing diets (250 mg, 6 g, 200 mg, and 1.5 g/kg diet, respectively) were studied in vivo. When KK mice were food deprived for 48 h and subsequently refed a fat-free diet for 72 h, hepatic triglyceride (TG) accumulation was significantly lower in mice fed CASL compared with the control mice. In addition, after obese KK mice were fed a low-fat diet for 2 wk, adipose tissue weights were significantly lower in those fed CASL, but not CA or SL alone, compared with the control mice. Plasma and liver TG levels were also lower in mice fed CASL than in the control mice. These results suggest that CASL is effective for controlling obesity.
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PMID:A combination of caffeine, arginine, soy isoflavones, and L-carnitine enhances both lipolysis and fatty acid oxidation in 3T3-L1 and HepG2 cells in vitro and in KK mice in vivo. 1788 7


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