Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The steroid hormone 20-hydroxyecdysone (20HE) is an essential signaling molecule that modulates molting response in insects and may function as a putative anabolic factor in vertebrate animals, although no mammalian 20HE receptor has been identified. Here we show that in H4IIE cell culture, 20HE treatment decreased expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), reduced glucose production, and induced Akt2 phosphorylation sensitive to the phosphoinositide-3 kinase pathway-specific inhibitor LY-294002. Daily oral administration of 20HE (10 mg/kg for 13 wk) ameliorated obesity and insulin resistance in C57BL/6J mice fed a high-fat diet and produced a significant decrease of body weight gain and body fat mass compared with nontreated animals as demonstrated by dual-energy X-ray absorptiometry analysis. In addition, plasma insulin levels and glucose tolerance were significantly lowered by 20HE treatment. These changes were accompanied by the reduced hepatic expression of PEPCK and G6Pase and increased adiponectin production by visceral fat tissue. These studies demonstrate the anti-obesity and anti-diabetic effects of 20HE and begin to elucidate its putative cellular targets both in vitro and in vivo.
 ...
PMID:20-Hydroxyecdysone decreases weight and hyperglycemia in a diet-induced obesity mice model. 1912 84

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using (2)H(2)O, [U-(13)C(3)]propionate, and [3,4-(13)C(2)]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin (P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats (P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP (P < 0.003). Female obese cats had approximately 1.5 times higher fluxes through phosphoenolpyruvate carboxykinase (P < 0.02) and citrate synthase (P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold (P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.
 ...
PMID:The impact of obesity, sex, and diet on hepatic glucose production in cats. 1919 46

PGC-1alpha expression is a tissue-specific regulatory feature that is extremely relevant to diabetes. Several studies have shown that PGC-1alpha activity is atypically activated in the liver of diabetic rodents and contributes to hepatic glucose production. PGC-1alpha and Foxo1 can physically interact with one another and represent an important signal transduction pathway that governs the synthesis of glucose in the liver. However, the effect of physical activity on PGC-1alpha/Foxo1 association is unknown. Here we investigate the expression of PGC-1alpha and the association of PGC-1alpha/Foxo1 in the liver of diet-induced obese rats after acute exercise. Wistar rats swam for two 3 h-long bouts, separated by a 45 min rest period. Eight hours after the acute exercise protocol, the rats were submitted to an insulin tolerance test (ITT) and biochemical and molecular analysis. Results demonstrate that acute exercise improved insulin signalling, increasing insulin-stimulated Akt and Foxo1 phosphorylation and decreasing PGC-1alpha expression and PGC-1alpha/Foxo1 interaction in the liver of diet-induced obesity rats under fasting conditions. These phenomena are accompanied by a reduction in the expression of gluconeogenesis genes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphate (G6Pase). Thus, these results provide new insights into the mechanism by which exercise could improve fasting hyperglycaemia.
 ...
PMID:Acute exercise modulates the Foxo1/PGC-1alpha pathway in the liver of diet-induced obesity rats. 3031 97

The glucocorticoid activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is of major interest in obesity-related morbidity. Alterations in tissue-specific cortisol levels may influence lipogenetic and gluco/glyceroneogenetic pathways in fat and liver. We analyzed the expression and activity of 11betaHSD1 as well as the expression of phosphoenolpyruvate carboxykinase (PEPCK), sterol regulatory element binding protein (SREBP), and fatty acid synthase (FAS) in adipose and liver and investigated putative associations between 11betaHSD1 and energy metabolism genes. A total of 33 obese women (mean BMI 44.6) undergoing gastric bypass surgery were enrolled. Subcutaneous adipose tissue (SAT), omental fat (omental adipose tissue (OmAT)), and liver biopsies were collected during the surgery. 11betaHSD1 gene expression was higher in SAT vs. OmAT (P = 0.013), whereas the activity was higher in OmAT (P = 0.009). The SAT 11betaHSD1 correlated with waist circumference (P = 0.045) and was an independent predictor for the OmAT area in a linear regression model. Energy metabolism genes had AT depot-specific expression; higher leptin and SREBP in SAT than OmAT, but higher PEPCK in OmAT than SAT. The expression of 11betaHSD1 correlated with PEPCK in both AT depots (P = 0.05 for SAT and P = 0.0001 for OmAT). Hepatic 11betaHSD1 activity correlated negatively with abdominal adipose area (P = 0.002) and expression positively with PEPCK (P = 0.003). In human obesity, glucocorticoid regeneration in the SAT is associated with central fat accumulation indicating that the importance of this specific fat depot is underestimated. Central fat accumulation is negatively associated with hepatic 11betaHSD1 activity. A disturbance in peripheral glucocorticoid metabolism is associated with changes in genes involved in fatty acid (FA) recycling in adipose tissue (AT).
Obesity (Silver Spring) 2009 Nov
PMID:Obesity is accompanied by disturbances in peripheral glucocorticoid metabolism and changes in FA recycling. 1936 9

TRB3 (a mammalian homolog of Drosophila) is emerging as an important player in the regulation of insulin signaling. TRB3 can directly bind to Ser/Thr protein kinase Akt, the major downstream kinase of insulin signaling. Conversely, physical exercise has been linked to improved glucose homeostasis and enhanced insulin sensitivity; however, the molecular mechanisms by which exercise improves glucose homeostasis, particularly in the hepatic tissue, are only partially known. Here, we demonstrate that acute exercise reduces fasting glucose in two models diabetic mice. Western blot analysis showed that 8 h after a swimming protocol, TRB3 expression was reduced in the hepatic tissue from diet-induced obesity (Swiss) and leptin-deficient (ob/ob) mice, when compared with respective control groups at rest. In parallel, there was an increase in insulin responsiveness in the canonical insulin-signaling pathway in hepatic tissue from DIO and ob/ob mice after exercise. In addition, the PEPCK expression was reduced in the liver after the exercise protocol, suggesting that acute exercise diminished hepatic glucose production through insulin-signaling restoration. Thus, these results provide new insights into the mechanism by which physical activity improves glucose homeostasis in type 2 diabetes.
 ...
PMID:Acute exercise reduces insulin resistance-induced TRB3 expression and amelioration of the hepatic production of glucose in the liver of diabetic mice. 1949 10

Free fatty acids (FFA) have been implicated as an important causative link between obesity, insulin resistance, and Type 2 diabetes. However, the underlying mechanisms especially for FFA-mediated hepatic insulin resistance are not fully elucidated. Here, we investigated the impaired sites in insulin signaling pathways and mechanisms of insulin resistance induced by elevated FFA in L02 hepatocytes. L02 cells were cultured in Dulbecco's modified eagle medium containing various concentrations of palmitic acid (PA) for 24 h followed by 10(-7) mol/l insulin stimulation. In some experiments, cells were pre-treated with enzymatic inhibitor Wortmannin (10(-6) mol/l). Glucose levels in medium, cytosolic glycogen contents, and phosphoenolpyruvate carboxykinase (PEPCK) activity were measured. Protein level of insulin receptor substrate (IRS)-2 and phosphorylated Akt were detected by Western blot analysis. L02 cells treated with high levels of PA exhibited increased glucose levels, whereas hepatic glycogen contents were decreased in a dose-dependent manner as compared to the control cells. There was a significant attenuation of IRS- 2 protein expression in the cells cultured with PA, and Wortmannin intervention exhibited different IRS-2 protein level with or without PA treatment. In accordance with the reduced IRS-2 level, the insulin-stimulated phosphorylation of Akt was diminished in the PA-treated cells. Basal PEPCK activity and insulin- regulated PEPCK activity were overstimulated in the cells incubated with PA. These data indicate high levels of FFA can disrupt glucose homeostasis, inflict some defects in insulin signaling, and induce insulin resistance in L02 cells.
 ...
PMID:Disruption of glucose homeostasis and induction of insulin resistance by elevated free fatty acids in human L02 hepatocytes. 1949 13

Exposure to maternal overnutrition increases the expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) in adipose tissue before birth, and it has been proposed that the precocial activation of PPARgamma target genes may lead to increased fat deposition in postnatal life. In this study, we determined the effect of intrafetal administration of a PPARgamma agonist, rosiglitazone, on PPARgamma target gene expression in fetal adipose tissue as well indirect actions of rosiglitazone on fetal liver and skeletal muscle. Osmotic pumps containing rosiglitazone (n = 7) or vehicle (15% ethanol, n = 7) were implanted into fetuses at 123-126 d gestation (term = 150 +/- 3 d gestation). At 137-141 d gestation, tissues were collected and mRNA expression of PPARgamma, lipoprotein lipase (LPL), adiponectin, and glycerol-3-phosphate dehydrogenase (G3PDH) in adipose tissue, PPARalpha and PPARgamma-coactivator 1alpha (PGC1alpha) in liver and muscle and phosphoenolpyruvate carboxykinase (PEPCK) in liver determined by quantitative real-time RT-PCR. Plasma insulin concentrations were lower in rosiglitazone-treated fetuses (P < 0.02). Rosiglitazone treatment resulted in increased expression of LPL and adiponectin mRNA (P < 0.01) in fetal adipose tissue. The expression of PPARalpha mRNA in liver (P < 0.05) and PGC1alpha mRNA (P < 0.02) in skeletal muscle were also increased by rosiglitazone treatment. Rosiglitazone treatment increased expression of PPARgamma target genes within fetal adipose tissue and also had direct or indirect actions on the fetal liver and muscle. The effects of activating PPARgamma in fetal adipose tissue mimic those induced by prenatal overnutrition, and it is therefore possible that activation of PPARgamma may be the initiating mechanism in the pathway from prenatal overnutrition to postnatal obesity.
 ...
PMID:Rosiglitazone increases the expression of peroxisome proliferator-activated receptor-gamma target genes in adipose tissue, liver, and skeletal muscle in the sheep fetus in late gestation. 1952 Jul 84

The metabolic effects of Roux-en-Y gastric bypass (RYGB) are caused by postsurgical changes in gastrointestinal anatomy affecting gut function. Glutamine is a critical gut nutrient implicated in regulating glucose metabolism as a substrate for intestinal gluconeogenesis. The present study examines the effects of obesity and RYGB on intestinal glutamine transport and metabolism. First, lean and obese Zucker rats (ZRs) were compared. Then the effects of RYGB and sham surgery with pair feeding (PF) in obese ZRs were studied. Segments of small intestine (biliopancreatic limb, Roux limb, and common channel) mucosa were harvested and brush border membrane vesicles (BBMVs) were isolated on postoperative day 28. Glutamine transporter activity and abundance, B(0)AT1 protein, and mRNA levels were measured. Levels of glutaminase, cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), and glucose-6-phosphatase (G6Pase) were measured to assess glutamine metabolism and intestinal gluconeogenesis. Obesity increased glutamine transport and B(0)AT1 expression throughout the intestine. RYGB increased glutamine transport activity in the biliopancreatic (3.8-fold) and Roux limbs (1.4-fold) but had no effect on the common channel. The relative abundance of B(0)AT1 mRNA and protein were increased in the biliopancreatic (6-fold) and Roux limbs (10-fold) after RYGB (P < 0.05 vs. PF), but not the common channel. Glutaminase levels were increased, whereas the relative abundance of PEPCK-C and G6Pase were decreased in all segments of intestine after RYGB. RYGB selectively increased glutamine absorption in biliopancreatic and Roux limbs by a mechanism involving increased B(0)AT1 expression. Post-RYGB glutaminase levels were increased, but the reductions in PEPCK-C and G6Pase suggest that RYGB downregulates intestinal gluconeogenesis.
 ...
PMID:Roux-en-Y gastric bypass alters small intestine glutamine transport in the obese Zucker rat. 1955 57

Circulating tumour necrosis factor-alpha (TNFalpha) levels, which are elevated in obesity-associated insulin resistance and diabetes, inhibit insulin signalling at several points in the signalling cascade. The liver is critical in maintaining circulating glucose levels and, in a preliminary investigation using the human hepatoma (HepG2) cell line in this study, we demonstrated the role of TNFalpha in the regulation of this phenomenon and determined the underlying molecular mechanisms. As the transcription factor Foxa2 has been implicated, in part, in the regulation of gluconeogenic genes, we studied the effects of TNFalpha and/or insulin on its cellular status in hepatocytes, followed by an assessment of its occupancy on the phosphoenolpyruvate carboxykinase (PEPCK) promoter. Preincubation of cells with TNFalpha, followed by insulin, significantly prevented insulin-mediated nuclear exclusion of Foxa2 and substantially increased its nuclear concentration. Foxa2 was subsequently found to occupy its binding element on the PEPCK promoter. TNFalpha alone, however, did not alter the status of cellular Foxa2 or its occupancy on the PEPCK promoter. TNFalpha preincubation also significantly attenuated insulin-induced inhibition of the expression of gluconeogenic enzymes and hepatic glucose production. Insulin inhibition of PEPCK expression and the preventive effect of TNFalpha could be partially but significantly restored in the presence of Foxa2 siRNA. Several other well-known mediators of insulin action in the liver in general and of gluconeogenic genes in particular include Foxo1, PGC-1 and SREBP-1c. Our results indicate that another transcription factor, Foxa2, is at least partly responsible for the attenuating effect of TNFalpha on insulin action on PEPCK expression and glucose production in HepG2 cells.
 ...
PMID:Tumour necrosis factor-alpha attenuates insulin action on phosphoenolpyruvate carboxykinase gene expression and gluconeogenesis by altering the cellular localization of Foxa2 in HepG2 cells. 1976 45

Obesity and type 2 diabetes are growing problems worldwide in adults and children. In this study, we focused on understanding the patterning of insulin resistance as a result of altered perinatal nutrition. We analyzed mice in which the binding site for PPARgamma was deleted from the promoter of the cytosolic phosphoenolpyruvate carboxykinase gene (Pck1) (PPARE(-/-)). We analyzed pups from dams with the same genotype as well as fostered and cross-fostered pups. Pck1 expression and triglyceride concentration in the milk were measured. The PPARE mutation reduced Pck1 expression in white adipose tissue (WAT) to 2.2% of wild type (WT) and reduced Pck1 expression in whole mammary gland tissue to 1% of WT. The female PPARE(-/-) mice had reduced lipid storage in mammary gland adipocytes and in WAT, resulting in a 40% reduction of milk triglycerides during lactation. Pups from PPARE(-/-) dams had insulin resistance as early as 14 d after birth, a condition that persisted into adulthood. WT pups fostered by PPARE(-/-) dams had lower body weights and plasma insulin concentrations compared with WT pups reared by WT dams. PPARE(-/-) pups fostered by WT dams had improved glucose clearance compared with pups raised by PPARE(-/-) dams. PPARE(+/-) and PPARE(-/-) dams also patterned newborn pups for reduced growth and insulin resistance in utero. Thus, the in utero environment and altered nutrition during the perinatal period cause epigenetic changes that persist into adulthood and contribute to the development of insulin resistance.
 ...
PMID:Reduced milk triglycerides in mice lacking phosphoenolpyruvate carboxykinase in mammary gland adipocytes and white adipose tissue contribute to the development of insulin resistance in pups. 1981 23


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>