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)

Increased oxidative stress is believed to be one of the mechanisms responsible for hyperglycemia-induced tissue damage and diabetic complications. In these studies, we undertook to characterize glucose uptake and oxidative stress in adipocytes of type 2 diabetic animals and to determine whether these promote the activation of PKC-delta. The adipocytes used were isolated either from C57Bl/6J mice that were raised on a high-fat diet (HF) and developed obesity and insulin resistance or from control animals. Basal glucose uptake significantly increased (8-fold) in HF adipocytes, and this was accompanied with upregulation of GLUT1 expression levels. Insulin-induced glucose uptake was inhibited in HF adipocytes and GLUT4 content reduced by 20% in these adipocytes. Reactive oxygen species (ROS) increased twofold in HF adipocytes compared with control adipocytes and were largely reduced with decreased glucose concentrations. At zero glucose, ROS levels were reduced to the normal levels seen in control adipocytes. The activity of PKC-delta increased twofold in HF adipocytes compared with control adipocytes and was further activated by H2O2. Moreover, PKC-delta activity was inhibited in HF adipocytes either by glucose deprivation or by treatment with the antioxidant N-acetyl-l-cysteine. In summary, we propose that increased glucose intake in HF adipocytes increases oxidative stress, which in turn promotes the activation of PKC-delta. These consequential events may be responsible, at least in part, for development of HF diet-induced insulin resistance in the fat tissue.
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PMID:Increased glucose uptake promotes oxidative stress and PKC-delta activation in adipocytes of obese, insulin-resistant mice. 1285 75

We examined the effect of six doses of dexamethasone (Dex) administered daily (2-7 days of age) to postnatal rats on body weight gain, food and water intake, peripheral hormonal/metabolic milieu, and hypothalamic neuropeptides that regulate food intake. We observed a Dex-induced acute (3 days of age) suppression of endogenous corticosterone and an increase in circulating leptin concentrations that were associated with a decrease in body weight in males and females. Followup during the suckling, postsuckling, and adult stages (7-120 days of age) revealed hypoleptinemia in males and females, and hypoinsulinemia, a relative increase in the glucose-to-insulin ratio, and a larger increase in skeletal muscle glucose transporter (GLUT 4) concentrations predominantly in the males, reflective of a catabolic state associated with a persistent decrease in body weight gain. The increase in the glucose-to-insulin ratio and hyperglycemia was associated with an increase in water intake. In addition, the changes in the hormonal/metabolic milieu were associated with an increase in hypothalamic neuropeptide Y content in males and females during the suckling phase, which persisted only in the 120-day-old female with a transient postnatal decline in alpha-melanocyte-stimulating hormone and corticotropin-releasing factor. This increase in neuropeptide Y (NPY) during the suckling phase in males and females was associated with a subsequent increase in adult food intake that outweighed the demands of body weight gain. In contrast to the adult hypothalamic findings, cerebral ventricular dilatation was more prominent in adult males. We conclude that postnatal Dex treatment causes permanent sex-specific changes in the adult phenotype, setting the stage for future development of diabetes (increased glucose:insulin ratio), obesity (increased NPY and food intake), and neurological impairment (loss of cerebral volume).
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PMID:Postnatal glucocorticoid exposure alters the adult phenotype. 1500 31

The increase in obesity in people and pets has been phenomenal. As in man, obesity in pets is a risk factor for many diseases including diabetes mellitus. Recently, tissue-specific regulation of glucose metabolism in fat and muscle tissue has been identified as an important factor for insulin sensitivity and it has been hypothesized that glucose uptake into tissues is altered in obesity causing insulin resistance. The purpose of this study was to determine the expression of the glucose transporter proteins GLUT4 and GLUT1 in muscle and fat from lean and obese cats. Seventeen domestic felines were tested in the lean state and again after a 6-month period of ad libitum food intake which led to a significant increase in weight (P < 0.0001). Obese cats showed a significantly higher area under the curve (AUC) for glucose, AUC for insulin and a significant decrease in glucose percentage disappearance per min (K-value) (P = 0.013, 0.018 and 0.017, respectively) during an intravenous glucose tolerance test, but no change in baseline glucose or glycosylated hemoglobin concentrations. GLUT4 expression was decreased in biopsies of both muscle (P = 0.002) and fat (P = 0.001) in the obese animals. GLUT4 in muscle and fat significantly and negatively correlated with the insulin AUC (r2 = 0.36, P = 0.004 and r2 = 0.18, P = 0.040, respectively). GLUT1 expression showed no significant change in the obese cats in either tissue. It is concluded that the changes in GLUT4 are early derangements in obesity and occur before glucose intolerance is clinically evident.
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PMID:GLUT4 but not GLUT1 expression decreases early in the development of feline obesity. 1506 22

The regulation of adipocyte metabolism is of importance for adipose tissue growth and therefore also for the development of obesity. This study was designed to investigate the regulation of basal and insulin-induced lipogenesis, glucose transport, and glucose transporter protein expression in human and rat adipocytes from different age groups. The study included 21 infants, 21 children, nine adults, and 80 male weaned and 20 male adult Fischer rats. The lipogenesis experiments were performed under conditions at which glucose transport is rate limiting. Basal lipogenesis was approximately three times higher in infants and children than in adults, whereas insulin-induced lipogenesis was two times higher in infants than in children and adults. In rats, basal lipogenesis, insulin-induced lipogenesis, and insulin sensitivity were two times higher in weaned than in adult animals. Moreover, basal and insulin-induced glucose transport were two times higher in weaned than in adult rats. No differences were detected in GLUT1 or GLUT4 content between any of the age groups in human or in rat adipocytes. In conclusion, basal and insulin-stimulated lipogenesis are increased in adipocytes early in life. This may promote adipose tissue growth in early age. The data indicate that age-dependent variation in basal and insulin-stimulated lipogenesis is differently regulated.
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PMID:Age-dependent regulation of lipogenesis in human and rat adipocytes. 1535 69

The facilitative glucose transporter, GLUT4, mediates insulin-stimulated glucose uptake in adipocytes and muscles, and the participation of GLUT4 in the pathogenesis of various clinical conditions associated with obesity, visceral fat accumulation and insulin resistance has been proposed. Glucose uptake by some members of the GLUT family, mainly GLUT1, is inhibited by flavonoids, the natural polyphenols present in fruits, vegetables and wine. Therefore it is of interest to establish if these polyphenolic compounds present in the diet, known to be effective antioxidants but also endowed with several other biological activities such as protein-tyrosine kinase inhibition, interfere with GLUT4 function. In the present study, we show that three flavonoids, quercetin, myricetin and catechin-gallate, inhibit the uptake of methylglucose by adipocytes over the concentration range of 10-100 microM. These three flavonoids show a competitive pattern of inhibition, with K(i)=16, 33.5 and 90 microM respectively. In contrast, neither catechin nor gallic acid inhibit methylglucose uptake. To obtain a better understanding of the interaction among GLUT4 and flavonoids, we have derived a GLUT4 three-dimensional molecular comparative model, using structural co-ordinates from a GLUT3 comparative model and a mechanosensitive ion channel [PDB (Protein Data Bank) code 1MSL] solved by X-ray diffraction. On the whole, the experimental evidence and computer simulation data favour a transport inhibition mechanism in which flavonoids and GLUT4 interact directly, rather than by a mechanism related to protein-tyrosine kinase and insulin signalling inhibition. Furthermore, the results suggest that GLUT transporters are involved in flavonoid incorporation into cells.
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PMID:Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes. 1546 17

Obesity is a major risk factor for Syndrome X and type II diabetes (T2D). However, most antidiabetic drugs that are hypoglycemic also promote weight gain, thus alleviating one symptom of T2D while aggravating a major risk factor that leads to T2D. Adipogenesis, the differentiation and proliferation of adipocytes, is a major mechanism leading to weight gain and obesity. It is highly desirable to develop pharmaceuticals and treatments for T2D that reduce blood glucose levels without inducing adipogenesis in patients. Previously, we reported that an extract from Lagerstroemia speciosa L. (banaba) possessed activities that both stimulated glucose transport and inhibited adipocyte differentiation in 3T3-L1 cells. Using glucose uptake assays and Western/Northern blot analyses as major tools and 3T3-L1 cells as a model, we showed that the banaba extract (BE) with tannin removed was devoid of the 2 activities, and tannic acid (TA), a major component of tannins, had the same 2 activities as BE. Inhibitors known to abolish insulin-induced glucose transport also blocked TA-induced glucose transport. We further detected that TA induced phosphorylation of the insulin receptor (IR) and Akt, as well as translocation of glucose transporter 4 (GLUT 4), the protein factors involved in the signaling pathway of insulin-mediated glucose transport. We also demonstrated that TA inhibited the expression of key genes for adipogenesis. Differences between samples with or without TA in all of the quantitative assays were significant (P < 0.05). These results suggest that TA may be useful for the prevention and treatment of T2D and its associated obesity. TA may have the potential to become the lead compound in the development of new types of antidiabetic pharmaceuticals that are able to reduce blood glucose levels without increasing adiposity.
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PMID:Tannic acid stimulates glucose transport and inhibits adipocyte differentiation in 3T3-L1 cells. 1567 Dec 8

Obesity is associated with impaired insulin-stimulated glucose disposal in the skeletal muscle, but whether this is an intrinsic or acquired factor is unknown. In many patients with type 2 diabetes mellitus (T2D) and their nondiabetic relatives, who have a genetic predisposition for diabetes, insulin resistance is maintained in cultured muscle cells. To study the association of obesity with defects in insulin action, we investigated insulin stimulation of both insulin receptor (IR) autophosphorylation and subsequent glucose transport in primary skeletal muscle cell cultures obtained from both nonobese and obese nondiabetic subjects. In these 2 groups, there was no difference in the ability of insulin to induce autophosphorylation of the IR, phosphorylation of the downstream serine kinase Akt/PKB, or stimulation of glucose transport. Moreover, there were no major differences in cultured muscle cell content of either the IR, the IR antagonist PC-1, or GLUT 1 and GLUT 4. These data therefore indicate that the insulin resistance associated with obesity is not maintained in cultured muscle cells and suggest that this insulin resistance is an acquired feature of obesity.
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PMID:Analysis of insulin-stimulated insulin receptor activation and glucose transport in cultured skeletal muscle cells from obese subjects. 1587 89

Body fat distribution determines obesity-related morbidity in adults but little is known of the aetiology or pathophysiology in children. This study investigates differences in insulin-mediated metabolism in primary cell cultures of subcutaneous and visceral preadipocytes derived from prepubertal children. The impact of differentiation and responses to TNFalpha exposure was also investigated. Proliferation rates were greater in subcutaneous versus visceral preadipocytes (41 h3 versus 69 h4; P=0.008). Insulin caused a dose-dependent increase in GSK-3 phosphorylation and an increase in MAPK phosphorylation over time, with increased sensitivity in subcutaneous preadipocytes. Post-differentiation, dose-dependent increases in GSK-3 phosphorylation were maintained, while MAPK phosphorylation was identical in both subtypes. No changes were observed in insulin receptor abundance pre-/post-differentiation. GLUT4 abundance was significantly increased in visceral versus subcutaneous adipocytes by 76(4)%; P=0.03), coincidental with increased insulin-stimulated 2-deoxy-glucose transport (+150(26)% versus +79(10)%; P=0.014) and further elevated by acute exposure to TNFalpha (+230(52)%; P=0.019 versus +123(24)%; P=0.025, respectively). TNFalpha also significantly increased basal glucose transport rates (+44(14)%; P=0.006 versus +34(11)%; P=0.007) and GLUT1 localisation to the plasma membrane. These data establish site-specific differences in subcutaneous and visceral fat cells from children. Responses to insulin varied with differentiation and TNFalpha exposure in the two depots, consistent with parallel changes in GLUT1/4 abundance and localisation.
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PMID:Site-specific differences of insulin action in adipose tissue derived from normal prepubertal children. 1593 53

We have developed a primary skeletal muscle cell culture model derived from normal prepubertal children to investigate the effects of insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and tumour necrosis factor alpha (TNFalpha) on growth, differentiation and metabolism. Cells of myoblast lineage were characterized morphologically by desmin staining and differentiated successfully into multinucleated myotubes. Differentiation was confirmed biochemically by an increase in creatine kinase (CK) activity and IGFBP-3 secretion over time. IGF-I promoted whilst TNFalpha inhibited myoblast proliferation, differentiation and IGFBP-3 secretion. IGF-I partially rescued the cells from the inhibiting effects of TNFalpha. Compared to adult myoblast cultures, children's skeletal muscle cells demonstrated higher basal and day 7 CK activities, increased levels of IGFBP-3 secretion, diminished IGF-I/TNFalpha action and absence of the inhibitory effect of exogenous IGFBP-3 on differentiation. Additional studies demonstrated that TNFalpha increased basal glucose transport via GLUT1, nitric oxide synthase and p38MAPK-dependent mechanisms. These studies provide baseline data to study the interactivity effects of growth factors and cytokines on differentiation and metabolism in muscle in relation to important metabolic disorders such as obesity, type II diabetes or chronic wasting diseases.
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PMID:Isolation and validation of human prepubertal skeletal muscle cells: maturation and metabolic effects of IGF-I, IGFBP-3 and TNFalpha. 1608 85

In this study, we examined whether the increased availability of lipids in blood resulting from two types of diet manipulation regulated metabolic gene expression in the skeletal muscle of rats. Feeding for 4 wk on an isocaloric-sucrose or a hypercaloric-fat diet increased plasma TAG in the fed condition by increments of 70 and 40%, respectively, and increased fasting insulinemia (approximately 3-fold) compared with a starch diet. The fat diet impaired glucose tolerance and caused obesity, whereas sucrose-fed rats maintained their normal weight. We analyzed the expression of genes that regulate the exogenous FA supply (LPL, FAT/CD36, FATP1), synthesis (ACC1), glucose (GLUT4, GLUT1, HK2, GFAT1, glycogen phosphorylase) or glycerol (glycerol kinase) provision, or substrate choice for oxidation (PDK4) in gastrocnemius and soleus muscles at the end of the glucose tolerance test. LPL, FAT/CD36, FATP1, PDK4, and GLUT4 mRNA as well as glycogen phosphorylase and glycerol kinase activity levels in both muscles were unchanged by the diets. Increased mRNA levels of GLUT1 (1.6- and 2.6-fold, respectively) and GFAT1 (about 1.7-fold) in gastrocnemius, and of ACC1 (about 1.5-fold) in soleus, were found in both the sucrose and fat groups. In the fat group, HK2 mRNA was also higher (1.8-fold) in the gastrocnemius. Both sucrose and saturated-fat diets prompted hyperinsulinemia and hyperlipemia in rats. These metabolic disturbances did not alter the expression of LPL, FAT/CD36, FATP1, PDK4, and GLUT4 genes or glycogen phosphorylase and glycerol kinase activity levels in either analyzed muscle. Instead, they were linked to the coordinated upregulation in gastrocnemius of genes that govern glucose uptake and the hexosamine pathway, namely, GLUT1 and GFAT1, which might contribute to insulin resistance.
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PMID:Effect of sucrose and saturated-fat diets on mRNA levels of genes limiting muscle fatty acid and glucose supply in rats. 1655 72


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