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

Overaccumulation of lipids in nonadipose tissues of obese rodents may lead to lipotoxic complications such as diabetes. To assess the pathogenic role of the lipogenic transcription factor, sterol regulatory element binding protein 1 (SREBP-1), we measured its mRNA in liver and islets of obese, leptin-unresponsive fa/fa Zucker diabetic fatty rats. Hepatic SREBP-1 mRNA was 2.4 times higher than in lean +/+ controls, primarily because of increased SREBP-1c expression. mRNA of lipogenic enzymes ranged from 2.4- to 4.6-fold higher than lean controls, and triacylglycerol (TG) content was 5.4 times higher. In pancreatic islets of fa/fa rats, SREBP-1c was 3.4 times higher than in lean +/+ Zucker diabetic fatty rats. The increase of SREBP-1 in liver and islets of untreated fa/fa rats was blocked by 6 weeks of troglitazone therapy, and the diabetic phenotype was prevented. Up-regulation of SREBP-1 also occurred in livers of Sprague-Dawley rats with diet-induced obesity. Hyperleptinemia, induced in lean +/+ rats by adenovirus gene transfer, lowered hepatic SREBP-1c by 74% and the lipogenic enzymes from 35 to 59%. In conclusion, overnutrition increases and adenovirus-induced hyperleptinemia decreases SREBP-1c expression in liver and islets. SREBP-1 overexpression, which is prevented by troglitazone, may play a role in the ectopic lipogenesis and lipotoxicity complicating obesity in Zucker diabetic fatty rats.
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PMID:Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. 1090 12

The corpulent JCR:LA-cp rat (cp/cp) is a useful model for study of the metabolic consequences of obesity and hyperinsulinemia. To assess the effect of hyperinsulinemia on VLDL secretion in this model, we measured rates of secretion of VLDL in perfused livers derived from cp/cp rats and their lean littermates. Livers of cp/cp rats secreted significantly greater amounts of VLDL triglyceride and apolipoprotein, compared with lean littermates. The content of apoB, apoE, and apoCs in both perfusate and plasma VLDL was greater in the cp/cp rat, as was the apolipoprotein (apo)C, apoA-I, and apoA-IV content of plasma HDL. Triglyceride content was also greater in cp/cp livers, as was hepatic lipogenesis and expression of lipogenic enzymes and sterol regulatory element binding protein-1 (SREBP-1). Hepatic mRNAs for apoE, and apoA-I were higher in livers of cp/cp rats. In contrast, the steady state levels of apoC-II, apoC-III, and apoB mRNAs were unchanged. Thus, livers of obese hyperinsulinemic cp/cp JCR:LA-cp rats secrete a greater number of VLDL particles that are enriched in triglyceride, apoE, and apoC. Greater secretion of VLDL in the cp/cp rat in part results from higher endogenous fatty acid synthesis, which in turn may occur in response to increased expression of the lipogenic enzyme regulator SREBP-1c.
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PMID:Increased hepatic VLDL secretion, lipogenesis, and SREBP-1 expression in the corpulent JCR:LA-cp rat. 1173 77

To determine whether increased lipogenesis contributes to human obesity, we measured (postabsorptive state), in lean and obese subjects, lipid synthesis (deuterated water method) and the mRNA concentration (RT-competitive PCR) in subcutaneous adipose tissue of fatty acid synthase (FAS) and sterol regulatory element-binding protein (SREBP)-1c. Before energy restriction, obese subjects had an increased contribution of hepatic lipogenesis to the circulating triglyceride pool (14.5 +/- 1.3 vs. 7.5 +/- 1.9%, P < 0.01) without enhancement of cholesterol synthesis. This increased hepatic lipogenesis represented an excess of 2-5 g/day of triglycerides, which would represent 0.7-1.8 kg on a yearly basis. The lipogenic capacity of adipose tissue appeared, on the contrary, decreased with lower FAS mRNA levels (P < 0.01) and a trend for decreased SREBP-1c mRNA (P = 0.06). Energy restriction in obese patients decreased plasma insulin (P < 0.05) and leptin (P < 0.05) and normalized hepatic lipogenesis. FAS mRNA levels were unchanged, whereas SREBP-1c increased. In conclusion, subjects with established obesity have an increased hepatic lipogenesis that could contribute to their excessive fat mass but no evidence for an increased lipogenic capacity of adipose tissue.
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PMID:Increased hepatic lipogenesis but decreased expression of lipogenic gene in adipose tissue in human obesity. 1173 82

Dietary digestible carbohydrates are able to modulate lipogenesis, by modifying the expression of genes coding for key lipogenic enzymes, like fatty acid synthase. The overall objective of the Nutrigene project (FAIR-CT97-3011) was to study the efficiency of various carbohydrates to modulate the lipogenic capacity and relevant gene expression in rat and human species (control and obese subjects) and to understand the underlying molecular mechanisms involved in the regulation of lipogenic genes by carbohydrates. Key cellular mediators (namely SREBP-1c and 2, AMP activated protein kinase, cholesterol content) of the regulation of lipogenic gene expression by glucose and/or insulin were identified and constitute new putative targets in the development of plurimetabolic syndrome associated with obesity. In humans, hepatic lipogenesis and triglyceride synthesis, assessed in vivo by the use of stable isotopes, was promoted by a high-carbohydrate diet in non obese subjects, and in non alcoholic steatotic patients, but was not modified in the adipose tissue of obese subjects. Non digestible/fermentable carbohydrates, such as fructans, were shown to decrease hepatic lipogenesis in non obese rats, and to lessen hepatic steatosis and body weight in obese Zucker rats. If confirmed in obese humans, this would allow the development of functional food able to counteract the metabolic disturbances linked to obesity.
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PMID:Study of the regulation by nutrients of the expression of genes involved in lipogenesis and obesity in humans and animals. 1189 44

Sterol regulatory element binding proteins (SREBPs) are transcription factors that are involved in adipogenesis and regulate the expression of genes controlling cholesterol and fatty acid biosynthesis. Animal experiments indicate that SREBP-1a, -1c, and -2 have distinct functions despite overlapping specificities for target genes. To study the possible relationships of SREBPs with obesity, we determined their expression levels in intra- and extraperitoneal adipose tissue samples of obese, post-obese and never-obese humans. We furthermore investigated possible associations of SREBP gene expression with mRNA levels of key enzymes of fatty acid and cholesterol biosynthesis. SREBP-1c was the most abundant SREBP mRNA isoform in human adipose tissue. mRNA levels of SREBP-1a and -1c correlated within tissues whereas no correlations were observed between SREBP-1a or -1c and SREBP-2 mRNA abundance. SREBP-1c and -2 mRNA levels were significantly lower in obese than in never-obese and post-obese subjects. SREBP-1c, but not -1a or -2 gene expression was associated with fatty acid synthase and acetyl-CoA carboxylase alpha gene expression in the intraperitoneal adipose tissue of obese humans. Our results suggest that common mechanisms are involved in the regulation of SREBP-1a and -1c expression in human adipose tissues and imply distinct functions of SREBP isoforms in the regulation of lipid and cholesterol biosynthesis. The reduction in SREBP-1c and -2 mRNA expression in obese humans and their upregulation after weight loss provides new insight into the relationship of these transcription factors with obesity in humans.
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PMID:Sterol regulatory element binding proteins: relationship of adipose tissue gene expression with obesity in humans. 1202 Aug 21

The tumor suppressor p53 is a transcription factor that activates or represses its target genes after various genotoxic stresses. We have previously shown that sterol regulatory element-binding protein-1 (SREBP-1), a key transcriptional regulator of triglyceride synthesis, and the lipogenic enzymes under its control are markedly suppressed in adipocytes from genetically obese ob/ob mice. Here we demonstrate that p53 and its target genes are highly induced in adipocytes of ob/ob mice in a fed state, leading to the negative regulation of SREBP-1 and thereby lipogenic genes. In fact, disruption of p53 in ob/ob mice completely suppressed the p53-regulated genes to wild-type levels and partially restored expression of lipogenic enzymes. Consistently, reporter gene analysis showed that p53 overexpression suppressed the promoter activity of the SREBP-1c gene and its downstream genes. Thus, the activation of p53 might constitute a negative feedback loop against excess fat accumulation in adipocytes. In conclusion, we discovered a novel role of p53 in the pathophysiology of obesity.
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PMID:p53 Activation in adipocytes of obese mice. 1273 85

This study identifies monocyte chemoattractant protein 1 (MCP-1) as an insulin-responsive gene. It also shows that insulin induces substantial expression and secretion of MCP-1 both in vitro in insulin-resistant (IR) 3T3-L1 adipocytes and in vivo in IR obese mice (ob/ob). Thus, MCP-1 resembles other previously described genes (e.g., PAI-1 and SREBP-1c) that remain sensitive to insulin in IR states. The hyperinsulinemia that frequently accompanies obesity and insulin resistance may therefore contribute to the altered expression of these and other genes in insulin target tissues. In vivo studies also demonstrate that MCP-1 is overexpressed in obese mice compared with their lean controls, and that white adipose tissue is a major source of MCP-1. The elevated MCP-1 may alter adipocyte function because addition of MCP-1 to differentiated adipocytes in vitro decreases insulin-stimulated glucose uptake and the expression of several adipogenic genes (LpL, adipsin, GLUT-4, aP2, beta3-adrenergic receptor, and peroxisome proliferator-activated receptor gamma). These results suggest that elevated MCP-1 may induce adipocyte dedifferentiation and contribute to pathologies associated with hyperinsulinemia and obesity, including type II diabetes.
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PMID:Monocyte chemoattractant protein 1 in obesity and insulin resistance. 1275 99

Adiponectin (Acrp30) is a physiologically active polypeptide hormone secreted by adipose tissue that shows insulin-sensitizing, antiinflammatory, and antiatherogenic properties. In humans, Acrp30 levels are inversely related to the degree of adiposity. In the current study, we tested the long-term weight-reducing and insulin-enhancing effects of Acrp30 cDNA delivered peripherally by a viral vector. To this end, we have generated a series of recombinant adeno-associated virus vectors of serotypes 1 and 5 encoding mouse Acrp30 cDNAs. The long-term expression of recombinant adeno-associated virus-Acrp30 vectors was tested after intramuscular or intraportal injection in female Sprague-Dawley rats with diet-induced obesity. We show that a single peripheral injection of 10(12) physical particles of Acrp30-encoding vectors resulted in sustained (up to 280 days) significant reduction in body weight, concomitant with the reduction in daily food intake. Acrp30 treatment resulted in higher peripheral insulin sensitivity measured by the i.p. glucose tolerance test in fasted animals. Ectopic expression of the Acrp30 transgene resulted in modulation of hepatic gluconeogenesis and lipogenesis, as demonstrated by the reduction of the expression of two key genes: PEPCK (phosphoenolpyruvate carboxykinase) and SREBP-1c (sterol regulatory element-binding protein 1c) in the liver. These data show successful peripheral therapy in a clinically relevant model for human obesity and insulin resistance.
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PMID:Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats. 1461 71

Insulin resistance, obesity, diabetes, dyslipidemia, and nonalcoholic fatty liver are components of the metabolic syndrome, a disease complex that is increasing at epidemic rates in westernized countries. Although proinflammatory cytokines have been suggested to contribute to the development of these disorders, the molecular mechanism is poorly understood. Here we show that overexpression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3 in liver causes insulin resistance and an increase in the key regulator of fatty acid synthesis in liver, sterol regulatory element-binding protein (SREBP)-1c. Conversely, inhibition of SOCS-1 and -3 in obese diabetic mice improves insulin sensitivity, normalizes the increased expression of SREBP-1c, and dramatically ameliorates hepatic steatosis and hypertriglyceridemia. In obese animals, increased SOCS proteins enhance SREBP-1c expression by antagonizing STAT3-mediated inhibition of SREBP-1c promoter activity. Thus, SOCS proteins play an important role in pathogenesis of the metabolic syndrome by concordantly modulating insulin signaling and cytokine signaling.
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PMID:Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. 1524 Aug 80

In the corpulent James C. Russell corpulent (JCR:LA-cp) rat, hyperinsulinemia leads to induction of lipogenic enzymes via enhanced expression of sterol-regulatory-binding protein (SREBP)-1c. This results in increased hepatic lipid production and hypertriglyceridemia. Information regarding down-regulation of SREBP-1c and lipogenic enzymes by dietary fatty acids in this model is limited. We therefore assessed de novo hepatic lipogenesis and hepatic and plasma lipids in corpulent JCR rats fed diets enriched in olive oil or menhaden oil. Using microarray and Northern analysis, we determined the effect of these diets on expression of mRNA for lipogenic enzymes and other proteins related to lipid metabolism. In corpulent JCR:LA-cp rats, both the olive oil and menhaden oil diets reduced expression of SREBP-1c, with concomitant reductions in hepatic triglyceride content, lipogenesis, and expression of enzymes related to lipid synthesis. Unexpectedly, expression of many peroxisomal proliferator-activated receptor-dependent enzymes mediating fatty acid oxidation was increased in livers of corpulent JCR rats. The menhaden oil diet further increased expression of these enzymes. Induction of SREBP-1c by insulin is dependent on liver x receptor (LXR)alpha. Although hepatic expression of mRNA for LXR itself was not increased in corpulent rats, expression of Cyp7a1, an LXR-responsive gene, was increased, suggesting increased LXR activity. Expression of mRNA encoding fatty acid translocase and ATP-binding cassette subfamily DALD member 3 was also increased in livers of corpulent JCR rats, indicating a potential role for these fatty acid transporters in the pathogenesis of disordered lipid metabolism in obesity. This study clearly demonstrates that substitution of dietary polyunsaturated fatty acid for carbohydrate in the corpulent JCR:LA-cp rat reduces de novo lipogenesis, at least in part, by reducing hepatic expression of SREBP-1c and that strategies directed toward reducing SREBP-1c expression in the liver may mitigate the adverse effects of hyperinsulinemia on hepatic lipid production.
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PMID:Dietary olive oil and menhaden oil mitigate induction of lipogenesis in hyperinsulinemic corpulent JCR:LA-cp rats: microarray analysis of lipid-related gene expression. 1533 73


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