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)

Fatty acid synthase (EC 2. 3. 1. 85, abbr. FAS) is reported as a potential new therapeutic target for the treatment of obesity. Thirty one Chinese medicinal herbs used in weight reducing prescriptions of Traditional Chinese Medicine (TCM) were investigated for FAS inhibition. It was found that 17 of these herbs exhibited FAS inhibitor activity, and 9 were highly potent FAS inhibitors. The inhibitory potencies of the active components of tuber fleeceflower root, parasitic loranthus, green tea leaf and ginkgo leaf were similar to or greater than cerulenin and C75. The first three of these four herbs significantly reduced body weight of rats upon their oral incubation. Moreover, tuber fleeceflower root and parasitic loranthus significantly reduced food intake in rats. These results indicate that many of weight reducing herbs used in TCM do so by inhibiting FAS. They also hold promise for the development of new nontoxic and low cost weight reducing substances from these herbs.
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PMID:Weight reduction by Chinese medicinal herbs may be related to inhibition of fatty acid synthase. 1499 16

C75, a synthetic inhibitor of FAS (fatty acid synthase), has both anti-tumour and anti-obesity properties. In this study we provide a detailed kinetic characterization of the mechanism of in vitro inhibition of rat liver FAS. At room temperature, C75 is a competitive irreversible inhibitor of the overall reaction with regard to all three substrates, i.e. acetyl-CoA, malonyl-CoA and NADPH, exhibiting pseudo-first-order kinetics of the complexing type, i.e. a weak non-covalent enzyme-inhibitor complex is formed before irreversible enzyme modification. C75 is a relatively inefficient inactivator of FAS, with a maximal rate of inactivation of 1 min(-1) and an extrapolated K(I) (dissociation constant for the initial complex) of approx. 16 mM. The apparent second-order rate constants calculated from these values are 0.06 mM(-1).min(-1) at room temperature and 0.21 mM(-1).min(-1) at 37 degrees C. We also provide experimental evidence that C75 inactivates the beta-ketoacyl synthase (3-oxoacyl synthase) partial activity of FAS. Unexpectedly, C75 also inactivates the enoyl reductase and thioesterase partial activities of FAS with about the same rates as for inactivation of the beta-ketoacyl synthase. In contrast with the overall reaction, the beta-ketoacyl synthase activity and the enoyl reductase activity, substrates do not protect the thioesterase activity of rat liver FAS from inactivation by C75. These results differentiate inactivation by C75 from that by cerulenin, which only inactivates the beta-ketoacyl synthase activity of FAS, by forming an adduct with an active-site cysteine. Interference by dithiothreitol and protection by the substrates, acetyl-CoA, malonyl-CoA and NADPH, further distinguish the mechanism of C75-mediated inactivation from that of cerulenin. The most likely explanation for the multiple effects observed with C75 on rat liver FAS and its partial reactions is that there are multiple sites of interaction between C75 and FAS.
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PMID:Characterization of the inactivation of rat fatty acid synthase by C75: inhibition of partial reactions and protection by substrates. 1571 22

In vitro studies suggest that the mitochondrial glycerol-3-phosphate acyltransferase-1 (mtGPAT1) isoform catalyzes the initial and rate-controlling step in glycerolipid synthesis and aids in partitioning acyl-CoAs toward triacylglycerol synthesis and away from degradative pathways. To determine whether the absence of mtGPAT1 would increase oxidation of acyl-CoAs and restrict the development of hepatic steatosis, we fed wild type and mtGPAT1-/- mice a diet high in fat and sucrose (HH) for 4 months to induce the development of obesity and a fatty liver. Control mice were fed a diet low in fat and sucrose (LL). With the HH diet, absence of mtGPAT1 resulted in increased partitioning of acyl-CoAs toward oxidative pathways, demonstrated by 60% lower hepatic triacylglycerol content and 2-fold increases in plasma beta-hydroxybutyrate, acylcarnitines, and hepatic mRNA expression of mitochondrial HMG-CoA synthase. Despite the increase in fatty acid oxidation, liver acyl-CoA levels were 3-fold higher in the mtGPAT1-/- mice fed both diets. A lack of difference in CPT1 and FAS mRNA expression between genotypes suggested that the increased acyl-CoA content was not because of increased de novo synthesis, but instead, to an impaired ability to use long-chain acyl-CoAs derived from the diet, even when the dietary fat content was low. Hyperinsulinemia and reduced glucose tolerance on the HH diet was greater in the mtGPAT1-/- mice, which did not suppress the expression of the gluconeogenic genes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This study demonstrates that mtGPAT1 is essential for normal acyl-CoA metabolism, and that the absence of hepatic mtGPAT1 results in the partitioning of fatty acids away from triacylglycerol synthesis and toward oxidation and ketogenesis.
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PMID:Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs. 1587 74

Recent studies have shown that FAS (fatty acid synthase) is a potential therapeutic target of obesity. In the present paper we report that extract of green tea (Camellia sinensis Xihu Longjing) inhibits FAS effectively with an IC50 value of 12.2 microg dry weight/ml. The ability of GTE (green tea extract) to inhibit FAS is more potent than that of two known inhibitors in green tea leaves, EGCG (epigallocatechin gallate) and ECG (epicatechin gallate). We find that (-)-CG (catechin gallate) is a very potent inhibitor of FAS, with an IC50 of 1.5 microg/ml, and may contribute to the high inhibitory effect of GTE on FAS. The inhibitory mechanism of (-)-CG is not mainly involved in its binding to the beta-oxoacyl reductase domain to which both (-)-EGCG and (-)-ECG mainly bind. By analyses of the inhibitory kinetics and the structure of the gallated catechins, we found that the acyl transferase domain may be the main site reacting with (-)-CG, the structure consisting of a B ring, a C ring and a gallate ring, which is possibly essential for its inhibitory efficacy. The polyphenols rather than the alkaloids are the main fractions contributing to the inhibitory effect of GTE on FAS. During separation we also found that the total ability of this portion to inhibit FAS increases by 15-fold, and this may be due to some novel potent inhibitor of FAS other than (-)-CG being formed.
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PMID:Novel inhibitors of fatty-acid synthase from green tea (Camellia sinensis Xihu Longjing) with high activity and a new reacting site. 1594 84

Systematic thin layer chromatographic (TLC) analysis of apolar lipids in Mycobacterium kansasii revealed the presence of a previously uncharacterized novel component. The product was ubiquitously found in a panel of M. kansasii clinical isolates, as well as other pathogenic and non-pathogenic mycobacterial species. TLC analysis of [(14)C]-acetate- or [(14)C]-glycerol-labelled M. kansasii cultures tentatively assigned the novel product as an unusual triacylglycerol-related lipid. Subsequent purification, followed by structural determination using (1)H-nuclear magnetic resonance (NMR) and electrospray mass spectrometry (ES/MS), led to the identification of this product as a monomeromycolyl-diacylglycerol (MMDAG). Treatment of M. kansasii with either isoniazid (INH), a well-known type II fatty acid synthase (FAS-II) and mycolic acid biosynthesis inhibitor, or tetrahydrolipstatin (THL), a drug approved for treating obesity, correlated with a reduced incorporation of [(14)C]-acetate into both mycolic acids and MMDAG. Addition of INH or THL to the cultures induced major morphological changes and, surprisingly, resulted in an increased number of lipid storage bodies, as determined by electron microscopy. The potent antimycobacterial activity of THL was confirmed against a variety of mycobacterial species, including INH-susceptible and -resistant Mycobacterium tuberculosis strains. Therefore, THL and other beta-lactones may be promising drugs for the development of new antitubercular therapy.
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PMID:Identification and structural characterization of an unusual mycobacterial monomeromycolyl-diacylglycerol. 1609 Oct 48

Euonymus alatus (EA), known as a Gui Jeon Wu in China, has been used as a folk medicine for regulating blood circulation, relieving pain, eliminating blood clot, and treating dysmenorrhea in Asian countries. Although EA has anecdotally ascertained to show the anti-hyperglycemic activity by enhancing insulin secretion, there is no sufficient experimental evidence for anti-hyperglycemic activity of EA. The purpose of this study was to investigate the preventive effect of 50% ethanol extract of EA in high-fat diet-induced hyperglycemic and hyperlipidemic ICR mice. At 6 week old, the ICR mice were randomly divided into five groups; two control and three treatment groups. The control mice was to receive either a regular diet (RD) or high-fat diet (HFD), and the treatment groups were fed a high-fat diet with either 350, 700 mg/kg of EA (EA350 and EA700) or 250 mg/kg of metformin (MET250) for a 10-week period. EA not only reduced body weight in a dose dependent manner, but also corrected associated hyperinsulinemia and hyperlipidemia. EA exerted beneficial effects on glucose and lipid homeostasis in diabetes that are not secondary to its ability to decrease food intake but its specific effects on hepatic lipogenesis related genes (SREBPla, FAS, GAPT) and PPAR-gamma gene expression in periepididymal fat. Taken together, the combined effect of EA to reduce plasma glucose and lipid levels, and reduce the deposition of triglyceride in the liver are indicative of a marked improvement in obesity-related diabetes and non-alcoholic fatty liver disease.
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PMID:Euonymus alatus prevents the hyperglycemia and hyperlipidemia induced by high-fat diet in ICR mice. 1609 53

ChREBP (Carbohydrate response element binding protein) is considered to mediate the stimulatory effect of glucose on the expression of lipogenic genes. Its activity is stimulated by glucose. Less is known on the control of its expression. This expression could be controlled by nutritional (glucose, fatty acids) and hormonal (insulin) factors. We examined the in vivo nutritional control of ChREBP expression in liver and adipose tissue of Wistar rats. Compared respectively to the fed state and to a high carbohydrate diet, ChREBP mRNA concentrations were not modified by fasting or a high fat diet in rat liver and adipose tissue. FAS and ACC1 mRNA concentrations were on the contrary decreased as expected by fasting and high fat diets and these variations of FAS and ACC1 mRNA were positively related to those of SREBP-1c mRNA and protein, but not of ChREBP mRNA. Therefore i) ChREBP expression appears poorly responsive to modifications of nutritional condition, ii) modifications of the expression of ChREBP do not seem implicated in the physiological control of lipogenesis. To investigate the possible role of ChREBP in pathological situations we measured its mRNA concentrations in the liver and adipose tissue of obese Zucker rats. ChREBP expression was increased in the liver but not the adipose tissue of obese rats compared to their lean littermates. These results support a role of ChREBP in the development of hepatic steatosis and hypertriglyceridemia but not of obesity in this experimental model.
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PMID:In vivo expression of carbohydrate responsive element binding protein in lean and obese rats. 1635 4

The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacological 11beta-HSD1 inhibition on the morphology and expression of key genes of lipid metabolism in intraabdominal adipose depots. Rats fed a high-sucrose, high-fat diet were treated or not with a specific 11beta-HSD1 inhibitor (compound A, 3 mg/kg.d) for 3 wk. Compound A did not alter food intake or body weight gain but specifically reduced mesenteric adipose weight (-18%) and adipocyte size, without significantly affecting those of epididymal or retroperitoneal depots. In mesenteric fat, the inhibitor decreased (to 25-50% of control) mRNA levels of genes involved in lipid synthesis (FAS, SCD1, DGAT1) and fatty acid cycling (lipolysis/reesterification, ATGL and PEPCK) and increased (30%) the activity of the fatty acid oxidation-promoting enzyme carnitine palmitoyltransferase 1. In striking contrast, in the epididymal depot, 11beta-HSD1 inhibition increased (1.5-5-fold) mRNA levels of those genes related to lipid synthesis/cycling and slightly decreased carnitine palmitoyltransferase 1 activity, whereas gene expression remained unaffected in the retroperitoneal depot. Compound A robustly reduced liver triacylglycerol content and plasma lipids. The study demonstrates that pharmacological inhibition of 11beta-HSD1, at a dose that does not alter food intake, reduces fat accretion specifically in the mesenterical adipose depot, exerts divergent intraabdominal depot-specific effects on genes of lipid metabolism, and reduces steatosis and lipemia.
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PMID:Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11beta-hydroxysteroid dehydrogenase type 1. 1727

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

Transgenic Late-onset OBesity (LOB) rats slowly develop a male-specific, autosomal dominant, obesity phenotype with a specific increase in peri-renal white adipose tissue (WAT) depot and preserved insulin sensitivity (Bains et al. in Endocrinology 145:2666-2679, 2004). To better understand the remarkable phenotype of these rats, the lipid metabolism was investigated in male LOB and non-transgenic (NT) littermates. Total plasma cholesterol (C) levels were normal but total plasma triacylglycerol (TAG) (2.8-fold) and hepatic TAG content (25%) was elevated in LOB males. Plasma VLDL-C and VLDL-TAG levels were higher while plasma apoB levels were 60% lower in LOB males. Increased hepatic TAG secretion explained the increased VLDL levels in LOB males. The hepatic gene expression of FAS, SCD-1, mitochondrial (mt)GPAT, and DGAT2 was up-regulated in both old obese and young non-obese LOB rats. Lipoprotein lipase (LPL) activity in heart and epididymal white adipose tissue (WAT) was unchanged, while LPL activity was increased in peri-renal WAT (30%) and decreased in soleus muscle (40%). Moreover, FAS, SCD-1 and DGAT2 gene expression was increased in peri-renal, but not in epididymal WAT. Basal lipolysis was reduced or unchanged and beta-adrenergic stimulated lipolysis was reduced in WAT from both old obese and young non-obese LOB rats. To summarize, the obese phenotype of LOB male rats is associated with increased hepatic TAG production and secretion, a shift in LPL activity from skeletal muscle to WAT, reduced lipolytic response in WAT depots and a specific increase in expression of genes responsible for fatty acid and TAG synthesis in the peri-renal depot.
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PMID:Hepatic and adipose tissue depot-specific changes in lipid metabolism in Late-onset Obese (LOB) rats. 1833 66


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