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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fatty acid elongases and desaturases play an important role in hepatic and whole body lipid composition. We examined the role that key transcription factors played in the control of hepatic elongase and desaturase expression. Studies with peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice establish that PPARalpha was required for WY14643-mediated induction of fatty acid elongase-5 (Elovl-5), Elovl-6, and all three desaturases [Delta(5) desaturase (Delta(5)D), Delta(6)D, and Delta(9)D]. Increased nuclear sterol-regulatory element binding protein-1 (SREBP-1) correlated with enhanced expression of Elovl-6, Delta(5)D, Delta(6)D, and Delta(9)D. Only Delta(9)D was also regulated independently by liver X receptor (LXR) agonist. Glucose induction of l-type pyruvate kinase, Delta(9)D, and Elovl-6 expression required the carbohydrate-regulatory element binding protein/MAX-like factor X (ChREBP/MLX) heterodimer. Suppression of Elovl-6 and Delta(9)D expression in livers of streptozotocin-induced diabetic rats and high fat-fed glucose-intolerant mice correlated with low levels of nuclear SREBP-1. In leptin-deficient obese mice (Lep(ob/ob)), increased SREBP-1 and MLX nuclear content correlated with the induction of Elovl-5, Elovl-6, and Delta(9)D expression and the massive accumulation of monounsaturated fatty acids (18:1,n-7 and 18:1,n-9) in neutral lipids. Diabetes- and obesity-induced changes in hepatic lipid composition correlated with changes in elongase and desaturase expression. In conclusion, these studies establish a role for PPARalpha, LXR, SREBP-1, ChREBP, and MLX in the control of hepatic fatty acid elongase and desaturase expression and lipid composition.
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PMID:Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity. 1679 Aug 40

A reduced brown adipose phenotype in white adipose tissue (WAT) may contribute to obesity and type 2 diabetes in humans. Retinoic acid, the carboxylic form of vitamin A, triggers in rodents a reduction of body weight and adiposity and an increased expression of uncoupling proteins in brown adipose tissue and skeletal muscle. In this study, we investigated possible remodeling effects of all-trans retinoic acid (ATRA) in WAT depots. Changes in the expression of genes related to thermogenesis and fatty acid oxidation and levels of phosphorylated retinoblastoma protein were analyzed in WAT depots of adult NMRI male mice acutely injected with ATRA or vehicle, together with biometric and blood parameters. Body fat loss after ATRA treatment was unaccompanied by any increase in circulating nonesterified fatty acids or ketone bodies and accompanied by increased rectal temperature. The treatment triggered an up-regulation of the mRNA levels of uncoupling proteins 1 and 2, peroxisome proliferator-activated receptor gamma coactivator-1alpha, peroxisome proliferator-activated receptor alpha, muscle- and liver-type carnitine palmitoyltransferase 1, and subunit II of cytochrome oxidase in different WAT depots. Levels of phosphorylated retinoblastoma protein in WAT depots were increased after ATRA treatment. Adipocyte size was reduced, and the number of multilocular adipocytes was increased in inguinal WAT of ATRA-treated mice. The results indicate that ATRA favors the acquisition of brown adipose tissue-like properties in WAT. Understanding the mechanisms and effectors involved in the remodeling of WAT can contribute to new avenues of prevention and treatment of obesity and type 2 diabetes.
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PMID:Remodeling of white adipose tissue after retinoic acid administration in mice. 1684 May 43

Physiological and pathophysiological conditions often affect the expression of drug metabolizing enzymes such as cytochromes P450 (P450s). Diabetes is one such factor and it is of great interest to understand its effects on drug metabolism, since diabetic patients generally have increased need for pharmacotherapy. We have recently reported the coordinated reduction of CYP2B1/2 and their transcriptional regulator constitutive androstane receptor (CAR), a member of the nuclear receptor superfamily, in the liver of genetically obese/diabetic Zucker fatty rats (Xiong, H., Yoshinari, K., et al., Drug Metab. Dispos., 30, 918-923, 2002). In this study, we investigated the expression of P450s and liver-enriched nuclear receptors in the liver of genetically diabetic db/db mice. Surprisingly, both CYP2B10 and CAR levels were increased in db/db mice. CYP4A expression was also increased at both mRNA and protein levels in db/db mice, while those of peroxisome proliferator-activated receptor alpha, a key regulator for the transcriptional activation of CYP4As, were comparable to those in age-matched C57BL/6 mice. Our results demonstrate that db/db mice and Zucker fatty rats exhibit different expression profiles of P450s and nuclear receptors despite their similar characteristics for obesity and diabetes resulting from a defect in the leptin signaling pathway.
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PMID:Changes in the expression of cytochromes P450 and nuclear receptors in the liver of genetically diabetic db/db mice. 1688 Jun 18

Recently it has become evident that obesity is associated with low-grade chronic inflammation. The transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) has been shown to have a strong antiinflammatory action in liver. However, the role of PPARalpha in obesity-induced inflammation is much less clear. Therefore, the aim of our study was to determine whether PPARalpha plays a role in obesity-induced hepatic inflammation. To induce obesity, wild-type sv129 and PPARalpha(-/-) mice were exposed to a chronic high-fat diet (HFD), using a low-fat diet (LFD) as control. In wild-type mice, HFD significantly increased the hepatic and adipose expression of numerous genes involved in inflammation. Importantly, this effect was amplified in PPARalpha(-/-) mice, suggesting an antiinflammatory role of PPARalpha in liver and adipose tissue. Further analysis identified specific chemokines and macrophage markers, including monocyte chemotactic protein 1 and F4/80(+), that were elevated in liver and adipose tissue of PPARalpha(-/-) mice, indicating increased inflammatory cell recruitment in the knockout animals. When all groups of mice were analyzed together, a significant correlation between hepatic triglycerides and expression of inflammatory markers was observed. Many inflammatory genes that were up-regulated in PPARalpha(-/-) livers by HFD were down-regulated by treatment with the PPARalpha ligand Wy-14643 under normal nonsteatotic conditions, either in vivo or in vitro, suggesting an antiinflammatory effect of PPARalpha that is independent of reduction in liver triglycerides. In conclusion, our results suggest that PPARalpha protects against obesity-induced chronic inflammation in liver by reducing hepatic steatosis, by direct down-regulation of inflammatory genes, and by attenuating inflammation in adipose tissue.
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PMID:Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation. 1734 5

Obesity-related diabetes mellitus leads to increased myocardial uptake of fatty acids (FAs), resulting in a form of cardiac dysfunction referred to as lipotoxic cardiomyopathy. We have shown previously that chronic activation of the FA-activated nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARalpha), is sufficient to drive the metabolic and functional abnormalities of the diabetic heart. Mice with cardiac-restricted overexpression of PPARalpha (myosin heavy chain [MHC]-PPARalpha) exhibit myocyte lipid accumulation and cardiac dysfunction. We sought to define the role of the long-chain FA transporter CD36 in the pathophysiology of lipotoxic forms of cardiomyopathy. MHC-PPARalpha mice were crossed with CD36-deficient mice (MHC-PPARalpha/CD36-/- mice). The absence of CD36 prevented myocyte triacylglyceride accumulation and cardiac dysfunction in the MHC-PPARalpha mice under basal conditions and following administration of high-fat diet. Surprisingly, the rescue of the MHC-PPARalpha phenotype by CD36 deficiency was associated with increased glucose uptake and oxidation rather than changes in FA utilization. As predicted by the metabolic changes, the activation of PPARalpha target genes involved in myocardial FA-oxidation pathways in the hearts of the MHC-PPARalpha mice was unchanged in the CD36-deficient background. However, PPARalpha-mediated suppression of genes involved in glucose uptake and oxidation was reversed in the MHC-PPARalpha/ CD36-/- mice. We conclude that CD36 is necessary for the development of lipotoxic cardiomyopathy in MHC-PPARalpha mice and that novel therapeutic strategies aimed at reducing CD36-mediated FA uptake show promise for the prevention or treatment of cardiac dysfunction related to obesity and diabetes.
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PMID:CD36 deficiency rescues lipotoxic cardiomyopathy. 1746 25

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a fatty acid-activated transcription factor that governs a variety of biological processes. Little is known about the role of PPARalpha in the small intestine. Since this organ is frequently exposed to high levels of PPARalpha ligands via the diet, we set out to characterize the function of PPARalpha in small intestine using functional genomics experiments and bioinformatics tools. PPARalpha was expressed at high levels in both human and murine small intestine. Detailed analyses showed that PPARalpha was expressed most highly in villus cells of proximal jejunum. Microarray analyses of total tissue samples revealed, that in addition to genes involved in fatty acid and triacylglycerol metabolism, transcription factors and enzymes connected to sterol and bile acid metabolism, including FXR and SREBP1, were specifically induced. In contrast, genes involved in cell cycle and differentiation, apoptosis, and host defense were repressed by PPARalpha activation. Additional analyses showed that intestinal PPARalpha-dependent gene regulation occurred in villus cells. Functional implications of array results were corroborated by morphometric data. The repression of genes involved in proliferation and apoptosis was accompanied by a 22% increase in villus height and a 34% increase in villus area of wild-type animals treated with WY14643. This is the first report providing a comprehensive overview of processes under control of PPARalpha in the small intestine. We show that PPARalpha is an important transcriptional regulator in small intestine, which may be of importance for the development of novel foods and therapies for obesity and inflammatory bowel diseases.
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PMID:Genome-wide analysis of PPARalpha activation in murine small intestine. 1742 15

Dehydroepiandrosterone (DHEA), the major precursor of androgens and estrogens, has several beneficial effects on the immune system, on memory function, and in modulating the effects of diabetes, obesity, and chemical carcinogenesis. Treatment of rats with DHEA influences expression of cytochrome P450 (P450) genes, including peroxisome proliferator-activated receptor alpha (PPAR alpha)- and pregnane X receptor (PXR)-mediated induction of CYP4As and CYP3A23, and suppression of CYP2C11. DHEA treatment elevated the expression and activities of CYP3A4, CYP2C9, CYP2C19, and CYP2B6 in primary cultures of human hepatocytes. Induction of CYP3A4 in human hepatocytes was consistent with studies in rats, but induction of CYP2Cs was unexpected. The role of PXR in this response was studied in transient transfection assays. DHEA activated hPXR in a concentration-dependent manner. Because CYP2B6 induction by DHEA in human hepatocytes might involve either PXR or constitutive androstane receptor (CAR) activation, we performed experiments in primary hepatocytes from CAR knockout mice and observed that CAR was required for maximal induction of Cyp2b10 by DHEA. Furthermore, CAR-mediated Cyp2b10 induction by DHEA was inhibited by the inverse agonist of CAR, androstanol (5 alpha-androstan-3 alpha-ol). Further evidence for CAR activation was provided by cytoplasmic/nuclear transfer of CAR upon DHEA treatment. Elucidation of CAR activation and subsequent induction of CYP2B6 by DHEA presented an additional mechanism by which the sterol can modify the expression of P450s. The effect of DHEA on the activation of the xenosensors PPAR alpha, PXR, and CAR, and the consequent potential for adverse drug/toxicant interactions should be considered in humans treated with this nutriceutical agent.
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PMID:Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor. 1759 76

The metabolic regulator fibroblast growth factor 21 (FGF21) has antidiabetic properties in animal models of diabetes and obesity. Using quantitative RT-PCR, we here show that the hepatic gene expression of FGF21 is regulated by the peroxisome proliferator-activated receptor alpha (PPARalpha). Fasting or treatment of mice with the PPARalpha agonist Wy-14,643 induced FGF21 mRNA by 10-fold and 8-fold, respectively. In contrast, FGF21 mRNA was low in PPARalpha deficient mice, and fasting or treatment with Wy-14,643 did not induce FGF21. Obese ob/ob mice, known to have increased PPARalpha levels, displayed 12-fold increased hepatic FGF21 mRNA levels. The potential importance of PPARalpha for FGF21 expression also in human liver was shown by Wy-14,643 induction of FGF21 mRNA in human primary hepatocytes, and PPARalpha response elements were identified in both the human and mouse FGF21 promoters. Further studies on the mechanisms of regulation of FGF21 by PPARalpha in humans will be of great interest.
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PMID:PPARalpha is a key regulator of hepatic FGF21. 1760 91

To investigate the effect of dietary 1,3-diacylglycerol (DAG) on the development of insulin resistance (IR) and obesity, brown adipose tissue-deficient mice, a model of high-fat diet-induced IR and obesity, were fed Western-type diets (WTD) containing either DAG oil (n = 8) or standard triacylglycerol (TAG) oil (n = 9) for 15 weeks, beginning at 8 weeks of age. Although brown adipose tissue-deficient mice became obese on both TAG- and DAG-enriched WTD (TAG-WTD and DAG-WTD), the mice eating DAG-WTD gained less weight and had less body fat accumulation. The results of glucose tolerance tests conducted after 5 weeks of each WTD were not different. However, after 10 weeks of each WTD, impaired glucose tolerance developed in the TAG-WTD group but was prevented by DAG-WTD. Exploratory analyses of gene expression suggested that consumption of DAG-WTD was associated with reduced phosphoenolpyruvate carboxykinase gene expression in liver and increased expression of the genes for peroxisome proliferator-activated receptor alpha, lipoprotein lipase, and uncoupling proteins 2 and 3 in skeletal muscle. There were no effects of the DAG-WTD on fasting and postprandial plasma triglyceride (TG) levels, hepatic TG content, or the rate of secretion of TG from the liver. These findings suggest that diets enriched in 1,3-DAG oil may reduce WTD-induced IR and body fat accumulation by suppressing gluconeogenesis in liver and stimulating fat oxidation in skeletal muscle.
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PMID:Dietary 1,3-diacylglycerol protects against diet-induced obesity and insulin resistance. 1795 Jan 9

Non-alcoholic steatohepatitis (NASH) is a hepatic manifestation of the metabolic syndrome that can progress to liver cirrhosis. The major aim of this study was to establish a novel NASH mouse model accompanied by obesity and insulin resistance, then explore the molecular mechanisms of NASH and evaluate the effects of both the peroxisome proliferator-activated receptor alpha (PPARalpha) agonist fenofibrate and the PPARgamma agonist rosiglitazone in this established NASH model. The novel model was induced in C57BL/6 mice by 23 weeks of ad libitum feeding of a modified high-fat diet (mHFD), with lower methinione and choline and higher fat content. In comparison to the controls, the model animals developed pronounced obesity, dyslipidemia and insulin resistance. Marked liver lesions characterized by severe steatosis, inflammation, fibrosis, increased hepatic triglyceride content, and elevated serum alanine aminotransferase (ALT) levels were observed in the models. In this novel model, treatment with fenofibrate or rosiglitazone significantly improved insulin sensitivity and corrected dyslipidemia; however, fenofibrate was more effective than rosiglitazone in improving hepatic morphology and ALT levels. Further study showed that long-term feeding of mHFD significantly increased expression of mRNA for hepatic PPARgamma, adipose fatty acid binding protein (ap2) and CD36 and suppressed expression of mRNA for hepatic PPARalpha and carnitine palmitoyl transferase-1a (CPT-1a). These results showed the successful establishment of the combined NASH and obese-insulin resistance mouse model. Additionally, aberrant expressions of hepatic PPARalpha and PPARgamma may play a major role in the pathogenesis of NASH by affecting hepatic lipogenesis and fatty acid oxidation in this novel model.
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PMID:The establishment of a novel non-alcoholic steatohepatitis model accompanied with obesity and insulin resistance in mice. 1841 55


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