UMLS:C0028754 - FACTA Search

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

Insulin resistance is often associated with obesity. We tested whether augmentation of triglyceride synthesis in adipose tissue by transgenic overexpression of the diacylglycerol aclytransferase-1 (Dgat1) gene causes obesity and/or alters insulin sensitivity. Male FVB mice expressing the aP2-Dgat1 had threefold more Dgat1 mRNA and twofold greater DGAT activity levels in adipose tissue. After 30 weeks of age, these mice had hyperglycemia, hyperinsulinemia, and glucose intolerance on a high-fat diet but were not more obese than wild-type littermates. Compared with control littermates, Dgat1 transgenic mice were both insulin and leptin resistant and had markedly elevated plasma free fatty acid levels. Adipocytes from Dgat1 transgenic mice displayed increased basal and isoproterenol-stimulated lipolysis rates and decreased gene expression for fatty acid uptake. Muscle triglyceride content was unaffected, but liver mass and triglyceride content were increased by 20 and 300%, respectively. Hepatic insulin signaling was suppressed, as evidenced by decreased phosphorylation of insulin receptor-beta (Tyr(1,131)/Tyr(1,146)) and protein kinase B (Ser473). Gene expression data suggest that the gluconeogenic enzymes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, were upregulated. Thus, adipose overexpression of Dgat1 gene in FVB mice leads to diet-inducible insulin resistance, which is secondary to redistribution of fat from adipose tissue to the liver in the absence of obesity.
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PMID:Whole-body insulin resistance in the absence of obesity in FVB mice with overexpression of Dgat1 in adipose tissue. 1630 52

We and others have previously shown that triple knockout mice lacking the beta1/beta2/beta3-adrenoceptors (beta-less mice) developed a progressive obesity at adulthood. Here, we studied the glucose homeostasis in beta-less mice before the onset of obesity. We show that beta-less mice have increased fat mass and are glucose intolerant. In addition, we observed that beta-less mice have impaired glucose-induced insulin secretion and exhibit an increase in liver PEPCK gene expression in the fed state, suggesting that they have increased gluconeogenesis. Although these characteristics are usually associated with insulin resistance, beta-less mice exhibit enhanced insulin sensitivity during insulin tolerance tests. This is keeping with the results obtained during euglycemic-hyperinsulinemic clamps showing that beta-less mice display increased insulin responsiveness with normal suppression of hepatic glucose production. Altogether, our results suggest that an intact beta-adrenergic system is required to regulate overall glucose homeostasis and, in particular, insulin-mediated glucose uptake, most likely at the level of muscles and adipose tissue.
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PMID:The lack of beta-adrenoceptors results in enhanced insulin sensitivity in mice exhibiting increased adiposity and glucose intolerance. 1630 66

Dehydroepiandrosterone (DHEA), the most abundant human adrenal steroid, improves insulin sensitivity and obesity in human and model animals. In a previous study, we reported that orally administered DHEA suppresses the elevated activities of hepatic gluconeogenic enzymes like glucose-6-phosphatase (G6Pase) in C57BL/KsJ-db/db mice. However, the molecular mechanisms by which DHEA ameliorates insulin resistance are not clearly understood. In the present study, we cultured the human hepatoma cell line HepG2 with DHEA and measured the enzyme activity and protein expression of G6Pase to investigate the direct effect of DHEA on glucose metabolism in hepatocytes. DHEA significantly suppressed both the activity and protein expression of G6Pase. Moreover, DHEA decreased the gene expression of G6Pase and phosphoenolpyruvate carboxykinase, both of which were maximal at 1 microM DHEA, whereas the mRNA level of glucose-6-phosphate translocase was unchanged. Furthermore, DHEA enhanced 2-deoxyglucose uptake, although its effect was much smaller than that of insulin. These results suggest that DHEA may act at multiple steps in the regulation of glucose metabolism in the liver.
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PMID:Effects of dehydroepiandrosterone on gluconeogenic enzymes and glucose uptake in human hepatoma cell line, HepG2. 1641 Jun 65

Obesity and insulin resistance are associated with increased serum free fatty acids (FFAs). Thus, a reduction in circulating FFAs may increase insulin sensitivity. This could be achieved by increasing FFA reesterification in adipose tissue. Transgenic mice with increased adipose tissue glyceroneogenesis, caused by overexpression of phosphoenolpyruvate carboxykinase (PEPCK), show increased FFA reesterification and develop obesity but are insulin sensitive. Here, we examined whether these transgenic mice were protected from diet-induced insulin resistance. Surprisingly, when fed a high-fat diet for a short period (6 weeks), transgenic mice developed severe obesity and were more hyperinsulinemic, glucose intolerant, and insulin resistant than controls. The high triglyceride accumulation prevented white adipose tissue from buffering the flux of lipids in circulation and led to increased serum triglyceride levels and fat deposition in liver. Furthermore, circulating leptin and FFA concentrations increased to similar levels in transgenic and control mice, while adiponectin levels decreased in transgenic mice compared with controls. In addition, transgenic mice showed fat accumulation in brown adipose tissue, which decreased uncoupling protein-1 expression, suggesting that these mice had impaired diet-induced thermogenesis. These results indicate that increased PEPCK expression in the presence of high-fat feeding may have deleterious effects and lead to severe insulin resistance and type 2 diabetes.
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PMID:Adipose overexpression of phosphoenolpyruvate carboxykinase leads to high susceptibility to diet-induced insulin resistance and obesity. 1644 57

Evidence to support an association between early nutrition and the development of obesity in the rat is equivocal. In this study we have investigated the postnatal growth, glucose tolerance, and adipocyte function of the offspring from pregnant rats fed with diets containing either 20% or 8% protein during gestation. By 25 weeks of age, the female offspring of dams fed with the diet containing 8% protein had a significantly lower adult body weight due in part to a decrease in body fat. The peak concentration of insulin after oral administration of a glucose dose was significantly lower in both the male and female offspring of the dams fed with the diet containing 8% protein. However, the ability of insulin to stimulate lipogenesis or suppress lipolysis in fat cells isolated from the offspring was not influenced by the prenatal diet. Hepatic phosphoenolpyruvate carboxykinase activity was reduced in female offspring of dams fed with the diet containing 8% protein. These results show that adult body composition is determined during the prenatal period as a result of programming of the insulin axis. This metabolic programming influences hepatic metabolism; however, there is no evidence for a programmed change in adipocyte function.
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PMID:Maternal protein intake in the pregnant rat programs the insulin axis and body composition in the offspring. 1663 41

Free fatty acids (FFA) are considered as a causative link between obesity and diabetes. In various animal models and in humans FFA can stimulate hepatic gluconeogenesis. Although the in vivo role of FFA in hepatic gluconeogenesis has been clearly established, the intracellular role of FFA and related signaling pathway remain unclear in the regulation of hepatic gluconeogenic gene transcription. In this study, we have identified p38 mitogen-activated protein kinase (p38) as a critical signaling component in FFA-induced transcription of key gluconeogenic genes. We show in primary hepatocytes that both mid- and long-chain fatty acids (saturated or unsaturated) could activate p38 and increase levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, and peroxisome proliferator-activated receptor gamma coactivator alpha (PGC-1alpha) gene transcripts. The FFA-induced expression of PEPCK and PGC-1alpha genes and gluconeogenesis in isolated hepatocytes could be blocked by the inhibition of p38. Furthermore, PGC-1alpha phosphorylation by p38 was necessary for FFA-induced activation of the PEPCK promoter. Additionally, FFA stimulated phosphorylation of cAMP-response element-binding protein (CREB) through p38. The overexpression of the dominant-negative CREB prevented FFA-induced activation of the PEPCK promoter. Finally, we show that FFA activation of p38 requires protein kinase Cdelta. Together, our results indicate that p38 plays a critical role in FFA-induced transcription of gluconeogenic genes, and the known gluconeogenic regulators, PGC-1alpha and CREB, are also integral parts of FFA-stimulated transcription of gluconeogenic genes.
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PMID:p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes. 1680 82

Fasting hyperglycemia, a prominent finding in diabetes, is primarily due to increased gluconeogenesis. The transcription factor Foxo1 links insulin signaling to decreased transcription of PEPCK and glucose-6-phosphatase (G6Pase) and provides a possible therapeutic target in insulin-resistant states. Synthetic, optimized antisense oligonucleotides (ASOs) specifically inhibit Foxo1 expression. Here we show the effect of such therapy on insulin resistance in mice with diet-induced obesity (DIO). Reducing Foxo1 mRNA expression with ASO therapy in mouse hepatocytes decreased levels of Foxo1 protein and mRNA expression of PEPCK by 48 +/- 4% and G6Pase by 64 +/- 3%. In mice with DIO and insulin resistance, Foxo1 ASO therapy lowered plasma glucose concentration and the rate of basal endogenous glucose production. In addition, Foxo1 ASO therapy lowered both hepatic triglyceride and diacylglycerol content and improved hepatic insulin sensitivity. Foxo1 ASO also improved adipocyte insulin action. At a tissue-specific level, this manifested as improved insulin-mediated 2-deoxyglucose uptake and suppression of lipolysis. On a whole-body level, the result was improved glucose tolerance after an intraperitoneal glucose load and increased insulin-stimulated whole-body glucose disposal during a hyperinsulinemic-euglycemic clamp. In conclusion, Foxo1 ASO therapy improved both hepatic insulin and peripheral insulin action. Foxo1 is a potential therapeutic target for improving insulin resistance.
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PMID:Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action. 1680 74

Peroxisome Proliferator-Activate Receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. The three PPARs (alpha, beta/delta, and gamma) are distributed differently in the different organs. PPARalpha is most common in the liver, but also found in kidney, gut, skeletal muscle and adipose tissue, while PPARbeta/delta, is fairly ubiquitous; it may be found in body tissues and brain (for myelination process and lipid metabolism in the brain). PPARgamma has 3 isoforms, such as PPARgamma 1, PPARgamma 2, and PPARgamma 3. The syndrome-X was firstly coined by Reaven in 1988 and then to be provided in 1999 by the name : the metabolic syndrome-X. This metabolic syndrome represents a "Cluster" of metabolic disorders and cardiovascular risk factors which has been collected and summarized by the author and such a cluster includes: insulin resistance/hyperinsulinemia, central obesity, glucose intolerance/DM, atherogenic dyslipidemia (increase TG, decrease HDL-cholesterol, increase Apo-B, increase small dense LDL), hypertension, prothrombotic state (increase PAI-1, increase F-VII, increase fibrinogen, increase vWF, increase adhesion molecules), endothelial dysfunction, hyperuricemia, and increased hsC-RP and cytokines. The metabolic syndrome-X may lead to the development of T2DM and coronary heart disease (CHD); insulin resistance plays pivotal roles in the progression of such a syndrome and cardiovascular diseases. Improvement of Insulin Resistance, therefore, is most likely to reduce the high cardiovascular event rate in T2DM. It has been generally accepted that Insulin Resistance (detected by HOMA-R) and Acute Insulin Response = AIR (by HOMA-B) are both usually present in T2DM. The Thiazolidinedions (TZDs) are Insulin Sensitizers (e.g Rosiglitazone = ROS, Pioglitazone = PIO) introduced into clinical practice in 1997; clinical evidence data showed that TZDs improved both HOMA-R, and HOMA-B. PPARgamma can be activated by TZDs and it appears to be fundamental to the pathophysiology of diabetes mellitus i.e increase GLUT-4, increase glucokinase, decrease PEPCK, increase GLUT-4, and decreases production by fat cell of several mediators that may cause insulin resistance, such as TNFalpha and resistin. PPARgamma also mediates increased production of Adiponectin and the insulin signaling intermediate PI3K, and both actions lead to increase insulin sensitivity. A "dual PPARgamma-PPARalpha agonists" (e.g PIO, but ROS poorly activate PPARalpha) might lower glucose and modulate lipids. Thus, PIO, as a stronger "dual PPARgamma-PPARalpha agonists", shows an important therapeutic pathway in diabetes mellitus and cardiovascular diseases, even in metabolic syndrome. Current evidence suggests a close relationship between activation of PPARgamma and restoration of insulin sensitivity by reductions in TNFalpha and FFAs, and the enhancement of insulin stimulation of PI3-K Pathway and also increase adiponectin & decrease resistin.
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PMID:New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer). 1711 68

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

Proopiomelanocortin (POMC) deficiency causes severe obesity through hyperphagia of hypothalamic origin. However, low glucocorticoid levels caused by adrenal insufficiency mitigate against insulin resistance, hyperphagia and fat accretion in Pomc-/- mice. Upon exogenous glucocorticoid replacement, corticosterone-supplemented (CORT) Pomc-/- mice show exaggerated responses, including excessive fat accumulation, hyperleptinaemia and insulin resistance. To investigate the peripheral mechanisms underlying this glucocorticoid hypersensitivity, we examined the expression levels of key determinants and targets of glucocorticoid action in adipose tissue and liver. Despite lower basal expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which generates active glucocorticoids within cells, CORT-mediated induction of 11beta-HSD1 mRNA levels was more pronounced in adipose tissues of Pomc-/- mice. Similarly, CORT treatment increased lipoprotein lipase mRNA levels in all fat depots in Pomc-/- mice, consistent with exaggerated fat accumulation. Glucocorticoid receptor (GR) mRNA levels were selectively elevated in liver and retroperitoneal fat of Pomc-/- mice but were corrected by CORT in the latter depot. In liver, CORT increased phosphoenolpyruvate carboxykinase mRNA levels specifically in Pomc-/- mice, consistent with their insulin-resistant phenotype. Furthermore, CORT induced hypertension in Pomc-/- mice, independently of adipose or liver renin-angiotensin system activation. These data suggest that CORT-inducible 11beta-HSD1 expression in fat contributes to the adverse cardiometabolic effects of CORT in POMC deficiency, whereas higher GR levels may be more important in liver.
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PMID:Peripheral mechanisms contributing to the glucocorticoid hypersensitivity in proopiomelanocortin null mice treated with corticosterone. 1759 30

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