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)

To elucidate the role of hormone-sensitive lipase (HSL) in diet-induced obesity, HSL-deficient (HSL-/-) and wild-type mice were fed normal chow or high-fat diets. HSL-/- mice were resistant to diet-induced obesity showing higher core body temperatures. Weight and triacylglycerol contents were decreased in white adipose tissue (WAT) but increased in both brown adipose tissue (BAT) and liver of HSL-/- mice. Serum insulin levels in the fed state and tumor necrosis factor-alpha mRNA levels in adipose tissues were higher, whereas serum levels of adipocyte complement-related protein of 30 kDa (ACRP30)/adiponectin and leptin, as well as mRNA levels of ACRP30/adiponectin, leptin, resistin, and adipsin in WAT, were lower in HSL-/- mice than in controls. Expression of transcription factors associated with adipogenesis (peroxisome proliferator-activated receptor-gamma, CAAT/enhancer-binding protein-alpha) and lipogenesis (carbohydrate response element-binding protein, adipocyte determination- and differentiation-dependent factor-1/sterol regulatory element-binding protein-1c), as well as of adipose differentiation markers (adipocyte lipid-binding protein, perilipin, lipoprotein lipase), lipogenic enzymes (glycerol-3-phosphate acyltransferase, acyl-CoA:diacylglycerol acyltransferase-1 and -2, fatty acid synthase, ATP citrate lyase) and insulin signaling proteins (insulin receptor, insulin receptor substrate-1, GLUT4), was suppressed in WAT but not in BAT of HSL-/- mice. In contrast, expression of genes associated with cholesterol metabolism (sterol-regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA:cholesterol acyltransferase-1) and thermogenesis (uncoupling protein-2) was upregulated in both WAT and BAT of HSL-/- mice. Our results suggest that impaired lipolysis in HSL deficiency affects lipid metabolism through alterations of adipose differentiation and adipose-derived hormone levels.
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PMID:Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice. 1295 98

Both environmental and genetic factors play important roles in the development of the metabolic syndrome. To elucidate how these factors interact under normal conditions, C57Bl/6 (B6) and 129S6/SvEvTac (129) mice were placed on a low-fat or high-fat diet. Over 18 weeks, the 129 strain developed features of the metabolic syndrome, notably obesity, hyperinsulinemia, and glucose intolerance only on the high-fat diet; the B6 strain on the other hand developed these features on both diets. High-fat feeding of both strains led to decreased serum triglycerides, hepatic steatosis, and hypercholesterolemia; however, B6 mice developed worse steatosis and a larger increase in LDL cholesterol. Both B6 background and high-fat feeding increased sterol regulatory element-binding protein-1c (SREBP-1c), a key regulator of lipogenic gene transcription, and its downstream targets. Stearoyl-CoA desaturase 1 (SCD1), an enzyme that regulates monounsaturated fatty acid (MUFA) synthesis, was also increased at the mRNA and enzyme activity levels by both high-fat feeding and B6 background. Furthermore, lipid analysis revealed increased hepatic triglycerides and MUFAs in B6 and high-fat-fed mice. Thus, dietary fat and genetic background act through SREBP-1c and SCD1 to affect hepatic lipid metabolism contributing to the development of the metabolic syndrome.
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PMID:Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome. 1585 15

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

Emerging evidence suggests that increased dietary consumption of fructose in Western society may be a potentially important factor in the growing rates of obesity and the metabolic syndrome. This review will discuss fructose-induced perturbations in cell signaling and inflammatory cascades in insulin-sensitive tissues. In particular, the roles of cellular signaling molecules including nuclear factor kappa B (NFkB), tumor necrosis factor alpha (TNF-alpha), c-Jun amino terminal kinase 1 (JNK-1), protein tyrosine phosphatase 1B (PTP-1B), phosphatase and tensin homolog deleted on chromosome ten (PTEN), liver X receptor (LXR), farnesoid X receptor (FXR), and sterol regulatory element-binding protein-1c (SREBP-1c) will be addressed. Considering the prevalence and seriousness of the metabolic syndrome, further research on the underlying molecular mechanisms and preventative and curative strategies is warranted.
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PMID:Fructose and the metabolic syndrome: pathophysiology and molecular mechanisms. 1760 9

Insulin resistance is a major pathological condition associated with obesity and metabolic syndrome. Insulin resistance and the renin-angiotensin system are intimately linked. We evaluated the role of the renin-angiotensin system in the pathogenesis of insulin resistance-associated, non-alcoholic steatohepatitis by using the angiotensin II type 1 receptor blocker olmesartan medoxomil in a diabetic rat model. The effects of olmesartan on methionine- and choline-deficient (MCD) diet-induced steatohepatitis were investigated in obese, diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats. Components of the renin-angiotensin system were up-regulated in the livers of OLETF rats, compared with LETO rats. In OLETF, but not LETO, rats, oral administration of olmesartan for 8 weeks ameliorated insulin resistance. Moreover, olmesartan suppressed MCD diet-induced hepatic steatosis and the hepatic expression of lipogenic genes (sterol regulatory element-binding protein-1c and fatty acid synthase) in OLETF, but not LETO, rats. In both OLETF and LETO rats, olmesartan inhibited hepatic oxidative stress (4-hydroxy-2-nonenal-modified protein) and expression of NADPH oxidase. Olmesartan also inhibited hepatic fibrosis, stellate cell activation, and expression of fibrogenic genes (transforming growth factor-beta, alpha 1 [I] procollagen, plasminogen activator inhibitor-1) in both OLETF and LETO rats. In conclusion, pharmacological blockade of the angiotensin II type 1 receptor slows the development of steatohepatitis in the OLETF rat model. This angiotensin II type 1 receptor blocker may exert insulin resistance-associated effects against hepatic steatosis and inflammation as well as direct effects against the generation of reactive oxygen species and fibrogenesis.
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PMID:Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects. 1850 44

The aim of present study was to identify the visceral adipose tissue genes differentially expressed in a well-characterized rat model of high-fat diet (HFD)-induced obesity. Male Sprague-Dawley rats were fed either the HFD (17 g lard + 3 g corn oil/100 g) or the normal diet (5 g corn oil/100 g) for 9 weeks. The HFD rats weighed 55% more and accumulated 85% to 133% greater visceral fats than did the normal-diet rats (P < .05). Animals given the HFD for 9 weeks acquired dyslipidemia, fatty liver, insulin resistance, and hyperleptinemia along with the overexpression of several obesity-related genes, such as leptin, tumor necrosis factor alpha, resistin, peroxisome proliferator-activated receptor gamma2, CCAAT/enhancer-binding protein alpha, and sterol regulatory element-binding protein-1c, in the epididymal adipose tissue. The differential gene expression profile obtained from the cDNA microarray analysis followed by the real-time polymerase chain reaction confirmation led to a recruitment of several uncharacterized adipose tissue genes responding to the HFD. We report herein, for the first time, that a series of genes which might be implicated in the insulin-stimulated glucose transporter 4 translocation, such as protein phosphatase 2 (formerly 2A), cell division cycle 42-interacting protein 4, syntaxin 6, linker of T-cell receptor pathways 10, as well as the genes which might be involved in cancer development, such as heat shock 10-kd protein 1, and ras-related C3 botulinum toxin substrate 1, were differentially expressed in the epididymal adipose tissue of rats rendered obese by an HFD.
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PMID:Genes are differentially expressed in the epididymal fat of rats rendered obese by a high-fat diet. 1908 40

Accumulation of lipids in the heart may cause cardiac dysfunction in various disorders, such as obesity and diabetes. In the current study, we have investigated whether administration of angiotensin II or norepinephrine induces accumulation of lipids and/or changes in the expression of genes related to lipid metabolism in the rat heart. Lipid deposition was found in myocardial, vascular wall, and perivascular cells of the angiotensin II-infused rat heart, and superoxide generation was increased in these lipid-positive cells. By contrast, intracardiac lipid deposition was not found in the heart of norepinephrine-induced hypertensive rats. Triglyceride content in the heart tissue of angiotensin II-infused rats increased more than 3-fold as compared with untreated controls. Losartan completely, but hydralazine only partially, suppressed the angiotensin II-induced intracardiac lipid deposition and increase in tissue triglyceride content. Administration of angiotensin II upregulated the mRNA expression of sterol regulatory element-binding protein-1c and fatty acid synthase, but downregulated that of uncoupling protein 2 and 3, in a manner dependent on the angiotensin AT(1) receptor. Collectively, these results suggest that angiotensin II may be involved in modulating both intracardiac lipid content and lipid metabolism-related gene expression, in part via an angiotensin AT(1) receptor-dependent and pressor-independent mechanism.
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PMID:Administration of angiotensin II, but not catecholamines, induces accumulation of lipids in the rat heart. 1910 42

Previous studies have shown that administration of fibroblast growth factor-19 (FGF-19) reverses diabetes, hepatic steatosis, hyperlipidemia, and adipose accretion in animal models of obesity. To investigate the mechanism for this effect, we determined whether FGF-19 modulated hepatic fatty acid synthesis, a key process controlling glucose tolerance and triacylglycerol accumulation in liver, blood, and adipose tissue. Incubating primary hepatocyte cultures with recombinant FGF-19 suppressed the ability of insulin to stimulate fatty acid synthesis. This effect was associated with a reduction in the expression of lipogenic enzymes. FGF-19 also suppressed the insulin-induced expression of sterol regulatory element-binding protein-1c (SREBP-1c), a key transcriptional activator of lipogenic genes. FGF-19 inhibition of lipogenic enzyme expression was not mediated by alterations in the activity of the insulin signal transduction pathway or changes in the activity of ERK, p38 MAPK, and AMP-activated protein kinase (AMPK). In contrast, FGF-19 increased the activity of STAT3, an inhibitor of SREBP-1c expression and decreased the expression of peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta), an activator of SREBP-1c activity. FGF-19 also increased the expression of small heterodimer partner (SHP), a transcriptional repressor that inhibits lipogenic enzyme expression via a SREBP-1c-independent mechanism. Inhibition of SREBP-1c activity by changes in STAT3 and PGC-1beta activity and inhibition of gene transcription by an elevation in SHP expression can explain the inhibition of lipogenesis caused by FGF-19. In summary, the inhibitory effect of FGF-19 on insulin activation of hepatic fatty acid synthesis constitutes a mechanism that would explain the beneficial effect of FGF-19 on metabolic syndrome.
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PMID:Fibroblast growth factor-19, a novel factor that inhibits hepatic fatty acid synthesis. 1923 43

Nonalcoholic fatty liver disease (NAFLD) is an abnormal liver metabolism often observed with insulin resistance and metabolic syndrome. Calorie restriction is a useful treatment for NAFLD and reportedly prolongs the life spans of several species in which sirtuin plays an important role. In this study, we examined whether the activation of SIRT1, a mammalian ortholog of sirtuin, may ameliorate the development of NAFLD. Monosodium glutamate (MSG) mice, which exhibited obesity and insulin resistance, were treated with SRT1720, a specific SIRT1 activator from the age of 6-16 wk. Sixteen-week-old MSG mice exhibited increased liver triglyceride content and elevated levels of aminotransferase. SRT1720 treatment significantly reduced these levels without affecting body weight or food intake. These results suggested that the administration of SRT1720 ameliorated the development of NAFLD in MSG mice. The expressions of lipogenic genes, such as sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase, and the serum lipid profiles, including free fatty acids, were elevated in MSG mice and were reduced by SRT1720 treatment. SRT1720 treatment also reduced the expressions of lipogenic genes in cultured HepG2 cells. Furthermore, SRT1720 treatment decreased the expressions of marker genes for oxidative stress and inflammatory cytokines in the liver of MSG mice. Taken together, SRT1720 treatment may reduce liver lipid accumulation, at least in part, by directly reducing the expressions of lipogenic genes. The reduction of oxidative stress and inflammation may also be involved in the amelioration of NAFLD.
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PMID:Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice. 1972 16

The primary objective of this study was to investigate the impact of lipid oversupply on the AMPK pathway in skeletal muscle, liver, and adipose tissue. Male Wistar rats were infused with lipid emulsion (LE) or phosphate-buffered saline for 5 h/day for 6 days. Muscles exposed to LE for 6 days exhibited increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation, along with a greater association between AMPK and Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK). No differences in muscle protein phosphatase 2C (PP2C) activity, LKB1 phosphorylation or AMPK and LKB1 association were observed. Muscle ACCbeta, and adiponectin receptor 1 (AdipoR1) mRNA levels and PPARgamma-co-activator 1alpha (PGC1alpha) protein levels were also increased in LE-treated rats. In contrast, AMPK and ACC phosphorylation decreased and PP2C activity increased in rat livers exposed to LE. Hepatic mRNA levels of ACCalpha, PPARalpha, AdipoR1, AdipoR2, and sterol regulatory element-binding protein-1c (SREBP1c) were also reduced after LE infusion. In adipose tissue, there was no significant alteration in AMPK or ACC phosphorylation. These results demonstrate that following lipid oversupply the AMPK pathway was enhanced in rat skeletal muscle while diminished in the liver and was unchanged in adipose tissue. CaMKK in skeletal muscle and PP2C in the liver, at least in part, appear to mediate these alterations. Alterations in AMPK pathway in the liver induced metabolic defects associated with lipid oversupply.
Obesity (Silver Spring) 2010 Jun
PMID:Infusion of a lipid emulsion modulates AMPK and related proteins in rat liver, muscle, and adipose tissues. 2005 67


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