scholarly journals Failure of insulin-regulated recruitment of the glucose transporter GLUT4 in cardiac muscle of obese Zucker rats is associated with alterations of small-molecular-mass GTP-binding proteins

1995 ◽  
Vol 311 (1) ◽  
pp. 161-166 ◽  
Author(s):  
I Uphues ◽  
T Kolter ◽  
B Goud ◽  
J Eckel
Keyword(s):  
Plasma Membranes ◽  
Microsomal Fraction ◽  
Glucose Transporter ◽  
Zucker Rats ◽  
Gtp Binding Protein ◽  
Insulin Resistant ◽  
Gtp Binding ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Glucose Transporter Glut4

Cardiac ventricular tissue of lean and genetically obese (fa/fa) Zucker rats was used to study the expression, subcellular distribution and insulin-induced recruitment of the glucose transporter GLUT4 and to elucidate possible molecular alterations of the translocation process. Hearts were removed from basal and insulin-treated (20 min) lean and obese Zucker rats, and processed for subcellular fractionation and Western blotting of proteins. In obese rats, the total GLUT4 content in a crude membrane fraction was reduced to 75 +/- 8% (P = 0.019) of lean controls. In contrast, GLUT4 abundance in plasma membranes was not significantly different between lean and obese rats with a concomitant decrease (47 +/- 3%) in the microsomal fraction of obese animals. In plasma membranes of lean animals insulin was found to increase the GLUT4 abundance to 294 +/- 43% of control with a significantly (P = 0.009) reduced effect in the obese group (139 +/- 10% of control). In these animals insulin failed to recruit GLUT4 from the microsomal fraction, whereas the hormone induced a significant decrease (41 +/- 4%) of microsomal GLUT4 in lean controls. In GLUT4-enriched membrane vesicles, obtained from cardiac microsomes of lean rats, a 24 kDa GTP-binding protein could be detected, whereas no significant labelling of this species was observed in GLUT4 vesicles prepared from obese animals. In addition to the translocation of GLUT4, insulin was found to promote the movement of the small GTP-binding protein rab4A from the cytosol (decrease to 61 +/- 13% of control) to the plasma membrane (increase to 177 +/- 19% of control) in lean rats with no effect of the hormone on rab4A redistribution in the obese group. In conclusion, cardiac glucose uptake of insulin-resistant obese Zucker rats is subject to multiple cellular abnormalities involving a reduced expression, altered redistribution and defective recruitment of GLUT4. We show here an association of the latter defect with alterations at the level of small GTP-binding proteins possibly leading to an impaired trafficking of GLUT4 in the insulin-resistant state.

Impaired Insulin-Induced Attenuation of Noradrenaline-Mediated Vasoconstriction in Insulin-Resistant Obese Zucker Rats

1997 ◽  
Vol 93 (3) ◽  
pp. 235-241 ◽  
Author(s):  
A. B. Walker ◽  
J. Dores ◽  
R. E. Buckingham ◽  
M. W. Savage ◽  
G. Williams
Keyword(s):  
Underlying Mechanism ◽  
Zucker Rats ◽  
Insulin Resistant ◽  
Obese Zucker Rat ◽  
Maximal Tension ◽  
Impaired Insulin ◽  
Obese Rats ◽  
Significant Impairment ◽  
Obese Zucker Rats ◽  
L 13

1. Insulin resistance is associated with hypertension but the underlying mechanism is unclear. We tested the hypothesis that insulin-induced vasodilatation is impaired in insulin-resistant obese Zucker rats. We studied mesenteric artery (≈ 220 μm diameter) function before the development of hypertension in 3-month old obese Zucker rats and age-matched lean rats. 2. In vessels from lean rats, insulin at concentrations of 50, 500 and 5000 m-units/l attenuated the constriction in response to noradrenaline (50 m-units/l: 8 ± 3%, P < 0.05; 500 m-units/l: 13 ± 3%, P < 0.02; 5000 m-units/l: 13 ± 2%, P < 0.02). 3. Vessels from obese rats failed to show any such response to insulin (2 ± 6% increase in maximal tension with 5000 m-units/l; not significant), both in the presence and absence of l-arginine (3 mmol/l). 4. Vessels from obese rats showed slight but significant impairment in the vasodilator response to acetylcholine (5 × 10−8−10−4 mol/l) (obese: 64.1 ± 3.7% relaxation; lean: 77.3 ± 3.7% relaxation; P < 0.05); however, relaxation in response to A23187 was not significantly different between the phenotypes (obese: 81.3 ± 10.6% relaxation; lean: 79.1 ± 9.7% relaxation; not significant). 5. Systolic blood pressure was not significantly different in lean (126 ± 8 mmHg) and obese (127 ± 7 mmHg) rats at the time of study (not significant). 6. We conclude that insulin-induced attenuation of noradrenaline-mediated vasoconstriction is impaired in the obese Zucker rat and that this defect precedes and therefore could contribute to the development of hypertension in this insulin-resistant model. The defect in insulin action could reside in the endothelial generation of nitric oxide, as endothelial function is also abnormal.

LKB1-AMPK signaling in muscle from obese insulin-resistant Zucker rats and effects of training

2006 ◽  
Vol 290 (5) ◽  
pp. E925-E932 ◽  
Author(s):  
Apiradee Sriwijitkamol ◽  
John L. Ivy ◽  
Christine Christ-Roberts ◽  
Ralph A. DeFronzo ◽  
Lawrence J. Mandarino ◽  
...  
Keyword(s):  
Protein Expression ◽  
Protein Content ◽  
Citrate Synthase ◽  
Zucker Rats ◽  
Ampk Signaling ◽  
Insulin Resistant ◽  
Ampk Pathway ◽  
Ampk Phosphorylation ◽  
Obese Rats ◽  
Obese Zucker Rats

AMPK is a key regulator of fat and carbohydrate metabolism. It has been postulated that defects in AMPK signaling could be responsible for some of the metabolic abnormalities of type 2 diabetes. In this study, we examined whether insulin-resistant obese Zucker rats have abnormalities in the AMPK pathway. We compared AMPK and ACC phosphorylation and the protein content of the upstream AMPK kinase LKB1 and the AMPK-regulated transcriptional coactivator PPARγ coactivator-1 (PGC-1) in gastrocnemius of sedentary obese Zucker rats and sedentary lean Zucker rats. We also examined whether 7 wk of exercise training on a treadmill reversed abnormalities in the AMPK pathway in obese Zucker rats. In the obese rats, AMPK phosphorylation was reduced by 45% compared with lean rats. Protein expression of the AMPK kinase LKB1 was also reduced in the muscle from obese rats by 43%. In obese rats, phosphorylation of ACC and protein expression of PGC-1α, two AMPK-regulated proteins, tended to be reduced by 50 ( P = 0.07) and 35% ( P = 0.1), respectively. There were no differences in AMPKα1, -α2, -β1, -β2, and -γ3 protein content between lean and obese rats. Training caused a 1.5-fold increase in AMPKα1 protein content in the obese rats, although there was no effect of training on AMPK phosphorylation and the other AMPK isoforms. Furthermore, training also significantly increased LKB1 and PGC-1α protein content 2.8- and 2.5-fold, respectively, in the obese rats. LKB1 protein strongly correlated with hexokinase II activity ( r = 0.75, P = 0.001), citrate synthase activity ( r = 0.54, P = 0.02), and PGC-1α protein content ( r = 0.81, P < 0.001). In summary, obese insulin-resistant rodents have abnormalities in the LKB1-AMPK-PGC-1 pathway in muscle, and these abnormalities can be restored by training.

scholarly journals Increased gene expression of lipogenic enzymes and glucose transporter in white adipose tissue of suckling and weaned obese Zucker rats

1991 ◽  
Vol 279 (1) ◽  
pp. 303-308 ◽  
Author(s):  
L Pénicaud ◽  
P Ferré ◽  
F Assimacopoulos-Jeannet ◽  
D Perdereau ◽  
A Leturque ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Glucose Transporter ◽  
Zucker Rats ◽  
Lipogenic Enzymes ◽  
Glut 4 ◽  
Obese Rats ◽  
Before And After ◽  
Plasma Insulin Levels ◽  
Obese Zucker Rats

Previous experiments have shown that insulin-induced glucose utilization is increased in white adipose tissue of young obese Zucker rats. We have investigated the possible role of over-expression of the muscle/fat glucose transporter (Glut 4) and key lipogenic enzymes in this increased insulin-responsiveness. The amount or activity and the mRNA concentrations of Glut 4, fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) were measured before and after weaning in white adipose tissue of obese and lean Zucker rats. Comparison of the levels of Glut 4 and lipogenic-enzyme expression in 15-day-old suckling and 30-day-old weaned rats on a high-carbohydrate diet shows a marked increase in the latter group. The increase was, in lean and obese rats respectively, 6- and 7-fold for the amount of Glut 4 and 2- and 3-fold for its mRNA concentrations, 40- and 100-fold for the activity of lipogenic enzymes (FAS and ACC) and 30- and 10-fold for their mRNA concentrations. Furthermore, all these parameters, except the amount of Glut 4, were 2-5-fold higher in obese rats, both before and after weaning. Changes at weaning were largely blunted when rats were weaned on to a high-fat diet, although the differences between lean and obese rats persisted, and even became significant for the amount of Glut 4. Whatever the experimental conditions, plasma insulin levels were significantly higher in obese than in lean rats. These results indicate the existence of an enhanced expression of Glut 4, FAS and ACC in white adipose tissue of young obese fa/fa rats which could be related to the increased plasma insulin levels.

Insulin sensitizer YM268 ameliorates insulin resistance by normalizing the decreased content of GLUT4 in adipose tissue of obese Zucker rats

1997 ◽  
pp. 693-700 ◽  
Author(s):  
A Shimaya ◽  
O Noshiro ◽  
R Hirayama ◽  
T Yoneta ◽  
K Niigata ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Transporter ◽  
Zucker Rats ◽  
Epididymal Adipose Tissue ◽  
Maximum Effect ◽  
Insulin Sensitizer ◽  
Peripheral Insulin Resistance ◽  
Obese Rats ◽  
Obese Zucker Rats

Genetically obese Zucker rats exhibit mild hyperglycaemia and hyperinsulinaemia suggesting the existence of peripheral insulin resistance. We have examined the effects of YM268, an analogue of thiazolidinedione, on the content and translocation of a glucose transporter (GLUT4) in epididymal adipose tissue in 11-week-old obese and lean Zucker rats. The administration of YM268 at a dose of 10 mg/kg for 2 weeks ameliorated hyperglycaemia, hyperinsulinaemia, and impaired glucose tolerance after glucose load in obese rats. The GLUT4 content per fat pad in obese rats was reduced to 36% of that in lean littermates. Obese rats treated with YM268 increased GLUT4 concentrations in their fat pads from a basal value of 36% up to 191% of the level in lean rats. Furthermore, in adipocytes prepared from obese rats, an increase in the ratio of GLUT4 in plasma membrane to the total amount of GLUT4 (PM-GLUT4 ratio) induced by the submaximal concentration of insulin (0.3 nmol/l) was significantly attenuated compared with that in lean rats. But the maximum effect of insulin (3 nmol/l) was not attenuated. Meanwhile, YM268 had no significant effect on the attenuated PM-GLUT4 ratio in response to insulin in obese rats. These data suggested that one of the mechanisms by which YM268 improved insulin resistance in obese Zucker rats was to normalize the decreased GLUT4 content in the adipose tissue.

scholarly journals Rab 3D in rat adipose cells and its overexpression in genetic obesity (Zucker fatty rat)

1997 ◽  
Vol 321 (1) ◽  
pp. 89-94 ◽  
Author(s):  
Michèle GUERRE-MILLO ◽  
Giulia BALDINI ◽  
Harvey F. LODISH ◽  
Marcelle LAVAU ◽  
Samuel W. CUSHMAN
Keyword(s):  
Molecular Basis ◽  
Plasma Membranes ◽  
Microsomal Fraction ◽  
Zucker Rats ◽  
Low Density ◽  
Secretory Function ◽  
Gtp Binding ◽  
Specific Manner ◽  
Intracellular Vesicles ◽  
Adipose Cells

Members of the Rab 3 subfamily of low-molecular-mass GTP-binding proteins have been functionally implicated in regulated exocytosis. The aim of the present study was to examine the subcellular distribution of a member of this family, Rab 3D, in rat adipose cells, given the hypothesis that this protein might be involved in insulin-stimulated GLUT4 exocytosis. We show that Rab 3D immunoreactivity is associated predominantly with the high-density microsomal fraction, where the signal intensity is 3-and 7-fold greater than that in plasma membranes and low-density microsomes respectively. Rab 3D does not co-localize with GLUT4 on immuno-isolated intracellular vesicles and, unlike GLUT4, it is not redistributed in response to insulin. Thus, if Rab 3D plays a role in GLUT4 trafficking, it relies on mechanisms independent of relocation. We observed that Rab 3D is overexpressed in adipose cells of obese (fa/fa) Zucker rats, in a tissue- and isoform-specific manner. The pathophysiological significance of this defect remains elusive. This could form the molecular basis for altered adipose secretory function in obesity.

Substrate utilization during acute exercise in obese Zucker rats

1990 ◽  
Vol 69 (6) ◽  
pp. 1987-1991 ◽  
Author(s):  
C. E. Torgan ◽  
J. T. Brozinick ◽  
M. E. Willems ◽  
J. L. Ivy
Keyword(s):  
Acute Exercise ◽  
Respiratory Exchange Ratio ◽  
Liver Glycogen ◽  
Zucker Rats ◽  
Insulin Resistant ◽  
Sedentary Group ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Glycogen Utilization ◽  
Total Muscle

The purpose of the present study was to compare the carbohydrate use of insulin-resistant obese Zucker rats with that of their lean littermates during steady-state exercise. Obese and lean rats were randomly assigned to a sedentary group or to a run group in which rats ran at 72-73% of their maximal O2 consumption, with the duration of exercise set to require an energy expenditure of 2.1-2.2 kcal. During the run the respiratory exchange ratio was significantly higher in the obese than in the lean rats [0.94 +/- 0.01 (SE) and 0.86 +/- 0.01, respectively], which indicate that the obese rats required 54% more carbohydrate than the lean rats. Total muscle glycogen utilization in the soleus, plantaris, and red and white gastrocnemius was not different between groups. Obese rats had total liver glycogen values five times greater than those of lean rats (833.38 +/- 101.4 and 152.8 +/- 37.5 mg, respectively) and utilized twice as much liver glycogen as their lean littermates (193.5 and 90.4 mg, respectively). The obese rats exhibited higher blood glucose and insulin concentrations than the lean rats during the run. These findings indicate that, despite their characteristic insulin resistance, the obese Zucker rats had a greater dependency on carbohydrate as a substrate during exercise than their lean littermates and that the major source of this carbohydrate was liver glycogen.

scholarly journals Obesity and Age-Related Changes in the Brain of the Zucker Lepr fa/fa Rats

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1356 ◽  
Author(s):  
Daniele Tomassoni ◽  
Ilenia Martinelli ◽  
Michele Moruzzi ◽  
Maria Vittoria Micioni Di Bonaventura ◽  
Carlo Cifani ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Body Weight Gain ◽  
Zucker Rats ◽  
Transporter Protein ◽  
Age Related ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Immunohistochemical Techniques ◽  
The Brain ◽  
Cognitive Alterations

Metabolic syndrome (MetS) is an association between obesity, dyslipidemia, hyperglycemia, hypertension, and insulin resistance. A relationship between MetS and vascular dementia was hypothesized. The purpose of this work is to investigate brain microanatomy alterations in obese Zucker rats (OZRs), as a model of MetS, compared to their counterparts lean Zucker rats (LZRs). 12-, 16-, and 20-weeks-old male OZRs and LZRs were studied. General physiological parameters and blood values were measured. Immunochemical and immunohistochemical techniques were applied to analyze the brain alterations. The morphology of nerve cells and axons, astrocytes and microglia were investigated. The blood–brain barrier (BBB) changes occurring in OZRs were assessed as well using aquaporin-4 (AQP4) and glucose transporter protein-1 (GLUT1) as markers. Body weight gain, hypertension, hyperglycemia, and hyperlipidemia were found in OZRs compared to LZRs. In the frontal cortex and hippocampus, a decrease of neurons was noticeable in the older obese rats in comparison to their age-matched lean counterparts. In OZRs, a reduction of neurofilament immunoreaction and gliosis was observed. The BBB of older OZRs revealed an increased expression of AQP4 likely related to the development of edema. A down-regulation of GLUT1 was found in OZRs of 12 weeks of age, whereas it increased in older OZRs. The behavioral analysis revealed cognitive alterations in 20-week-old OZRs. Based on these results, the OZRs may be useful for understanding the mechanisms through which obesity and related metabolic alterations induce neurodegeneration.

scholarly journals Contractile activity restores insulin responsiveness in skeletal muscle of obese Zucker rats

1993 ◽  
Vol 289 (2) ◽  
pp. 423-426 ◽  
Author(s):  
P L Dolan ◽  
E B Tapscott ◽  
P J Dorton ◽  
G L Dohm
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transport ◽  
Contractile Activity ◽  
Clinical Importance ◽  
Zucker Rats ◽  
Insulin Resistant ◽  
Significant Difference ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Insulin Responsiveness

Both insulin and contraction stimulate glucose transport in skeletal muscle. Insulin-stimulated glucose transport is decreased in obese humans and rats. The aims of this study were (1) to determine if contraction-stimulated glucose transport was also compromised in skeletal muscle of genetically obese insulin-resistant Zucker rats, and (2) to determine whether the additive effects of insulin and contraction previously observed in muscle from lean subjects were evident in muscle from the obese animals. To measure glucose transport, hindlimbs from lean and obese Zucker rats were perfused under basal, insulin-stimulated (0.1 microM), contraction-stimulated (electrical stimulation of the sciatic nerve) and combined insulin-(+)contraction-stimulated conditions. One hindlimb was stimulated to contract while the contralateral leg served as an unstimulated control. 2-Deoxyglucose transport rates were measured in the white gastrocnemius, red gastrocnemius and extensor digitorum longus muscles. As expected, the insulin-stimulated glucose transport rate in each of the three muscles was significantly slower (P < 0.05) in obese rats when compared with lean animals. When expressed as fold stimulation over basal, there was no significant difference in contraction-induced muscle glucose transport rates between lean and obese animals. Insulin-(+)contraction-stimulation was additive in skeletal muscle of lean animals, but synergistic in skeletal muscle of obese animals. Prior contraction increased insulin responsiveness of glucose transport 2-5-fold in the obese rats, but had no effect on insulin responsiveness in the lean controls. This contraction-induced improvement in insulin responsiveness could be of clinical importance to obese subjects as a way to improve insulin-stimulated glucose uptake in resistant skeletal muscle.

Modulation of noradrenaline-induced vasoconstriction in isolated perfused mesenteric arterial beds from obese Zucker rats in the presence and absence of insulin

2002 ◽  
Vol 80 (3) ◽  
pp. 171-179 ◽  
Author(s):  
Yi He ◽  
Kathleen M MacLeod
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Receptor Antagonist ◽  
Vascular Reactivity ◽  
Zucker Rats ◽  
Insulin Resistant ◽  
Significant Difference ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Presence And Absence

The genetically obese Zucker rat (fa/fa) is an insulin-resistant animal model with early-onset severe hyperinsulinemia that eventually develops mild hypertension. Thus, it represents a model in which the effect of hyperinsulinemia – insulin resistance associated with hypertension on vascular reactivity can be examined. The purpose of this study was to investigate the contribution of endogenous nitric oxide (NO) and prostaglandins to reactivity to noradrenaline (NA) in the presence and absence of insulin in mesenteric arterial beds (MAB) from 25-week-old obese Zucker rats and their lean, gender-matched littermates. In the absence of insulin, bolus injection of NA (0.9–90 nmol) produced a dose-dependent increase in perfusion pressure in MAB from both lean and obese rats. Although there was no significant difference in NA pD2 (–log ED50) values, the maximum response of MAB from obese rats to NA was slightly but significantly reduced compared with that of MAB from lean rats. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 300 µM) enhanced and indomethacin (20 µM) inhibited pressor responses to NA in MAB from both obese and lean rats. Perfusion with insulin (200 mU/L, a level similar to that in obese rats in vivo) potentiated only the responses of the obese MAB to the two lowest doses of NA tested (0.9 and 3 nmol). In the presence of L-NMMA, insulin further potentiated the NA response in MAB from obese rats. Indomethacin, the prostaglandin H2/thromboxane A2 receptor antagonist SQ 29548 (0.3 µM), and the nonselective endothelin-1 (ET-1) receptor antagonist bosentan (3 µM) all abolished insulin potentiation of the NA response in obese MAB. These data suggest that concurrent release of NO and vasoconstrictor cyclooxygenase product(s) in MAB from both obese and lean Zucker rats normally regulates NA-induced vasoconstrictor responses. Furthermore, insulin increases the release of contracting cyclooxygenase product(s) and enhances reactivity to low doses of NA in MAB from obese rats. The effects of insulin may be partially mediated by ET-1 via ET receptors and are buffered to some extent by concomitant NO release. This altered action of insulin may play a role in hypertension in this hyperinsulinemic – insulin-resistant model.Key words: hyperinsulinemia, insulin resistance, hypertensive Zucker obese rat, mesenteric arterial bed, noradrenaline.

Sign in / Sign up

Export Citation Format

Share Document