Skeletal muscle contraction stimulates capillary recruitment and glucose uptake in insulin-resistant obese Zucker rats

2004 ◽  
Vol 287 (4) ◽  
pp. E804-E809 ◽  
Author(s):  
Catherine M. Wheatley ◽  
Stephen Rattigan ◽  
Stephen M. Richards ◽  
Eugene J. Barrett ◽  
Michael G. Clark
Keyword(s):  
Muscle Contraction ◽  
Glucose Uptake ◽  
Lower Leg ◽  
Zucker Rats ◽  
Zucker Rat ◽  
Capillary Recruitment ◽  
Obese Zucker Rat ◽  
Impaired Insulin ◽  
Obese Zucker Rats

Exercise and insulin increase muscle glucose uptake by different mechanisms and also increase capillary recruitment, which is proposed to facilitate access for hormones and nutrients. The genetically obese Zucker rat shows impaired insulin- but not contraction-mediated glucose uptake in muscle. Recently, we have shown the genetically obese Zucker rats to have impaired insulin-mediated capillary recruitment and proposed that this contributes to the insulin resistance of muscle in vivo. Because this might imply a general loss of recruitable capillaries, we now assess responses to contraction in muscles of 18 ± 3-wk-old lean and obese Zucker rats in vivo. Field stimulation (2 Hz, 0.1 ms) was conducted for 1 h on one leg of anesthetized instrumented rats, and measurements were made of femoral blood flow (FBF), heart rate (HR), blood pressure (BP), hindleg metabolism of 1-methylxanthine (a measure of capillary recruitment), hindleg glucose uptake (HGU), and lower leg muscle glucose uptake by 2-deoxyglucose (R′g). Lean animals (311 ± 9 g) developed tension at 219 ± 27 g/g muscle with no change in BP but with significant increases in HR, FBF, HGU, 1-MX metabolism, and R′g ( P < 0.05), compared with nonstimulated control leans. Obese animals (469 ± 7 g) developed tension at 265 ± 31 g/g muscle with no change in HR or BP but with significant increases in FBF, HGU, 1-MX metabolism, and R′g ( P < 0.05) compared with nonstimulated control obese rats. Muscle contraction of lean animals led to a greater increase in lower leg R′g, similar responses in HGU and 1-MX, and a smaller increase in FBF than in obese animals. A tight correlation between FBF and capillary recruitment was noted for all data ( P < 0.001). It is concluded that contraction-mediated muscle capillary recruitment and glucose uptake are essentially normal in the obese Zucker rat and that control of FBF and capillary recruitment in exercise is closely linked.

scholarly journals The age-related increase in renal clusterin mRNA is accelerated in obese Zucker rats.

1998 ◽  
Vol 9 (1) ◽  
pp. 38-45 ◽  
Author(s):  
N J Laping ◽  
B A Olson ◽  
J R Day ◽  
B M Brickson ◽  
L C Contino ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Tissue Injury ◽  
Rat Kidney ◽  
Zucker Rats ◽  
Mrna Levels ◽  
Zucker Rat ◽  
Age Related ◽  
Obese Zucker Rat ◽  
Obese Zucker Rats ◽  
F344 Rats

Clusterin is a multifunctional glycoprotein associated with development and tissue injury. Because renal function decreases with advancing age in the obese Zucker rat, clusterin mRNA expression was examined in the kidney of young adult Zucker rats and compared with age-related changes in renal clusterin mRNA expression in Fischer 344 (F344) rats. Renal clusterin mRNA levels in the obese Zucker rat were 2.5-fold higher by 3 mo of age and fourfold higher at 5 mo of age compared with the lean strain. In comparison, renal clusterin mRNA in 12-mo-old F344 rats was twofold higher than in 3-mo-old animals and was tenfold higher at 24 mo of age. Clusterin mRNA was positively correlated with urinary protein excretion and negatively correlated with creatinine clearance in Zucker rats. Clusterin was increased in select nephrons of the obese Zucker rat kidney and in 24-mo-old F344 rat kidney as assessed by in situ hybridization. Increased expression of clusterin mRNA occurred mostly in the tubular epithelium of dilated, convoluted proximal tubules. These data indicate that renal clusterin mRNA levels increase as a function of age and that age-related increases in renal clusterin and the associated tubular abnormalities are accelerated in obese Zucker rats.

scholarly journals Mechanism controlling sleep organization of the obese Zucker rats

1998 ◽  
Vol 84 (1) ◽  
pp. 253-256 ◽  
Author(s):  
David Megirian ◽  
Jacek Dmochowski ◽  
Gaspar A. Farkas
Keyword(s):  
Eye Movement ◽  
Rem Sleep ◽  
Nrem Sleep ◽  
Zucker Rats ◽  
Rapid Eye Movement ◽  
Zucker Rat ◽  
Obese Zucker Rat ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
The Mean

Megirian, David, Jacek Dmochowski, and Gaspar A. Farkas. Mechanism controlling sleep organization of the obese Zucker rat. J. Appl. Physiol. 84(1): 253–256, 1998.—We tested the hypothesis that the obese ( fa/fa) Zucker rat has a sleep organization that differs from that of lean Zucker rats. We used the polygraphic technique to identify and to quantify the distribution of the three main states of the rat: wakefulness (W), non-rapid-eye-movement (NREM), and rapid-eye-movement (REM) sleep states. Assessment of states was made with light present (1000–1600), at the rats thermoneutral temperature of 29°C. Obese rats, compared with lean ones, did not show significant differences in the total time spent in the three main states. Whereas the mean durations of W and REM states did not differ statistically, that of NREM did ( P = 0.046). However, in the obese rats, the frequencies of switching from NREM sleep to W, which increased, and from NREM to REM sleep, which decreased, were statistically significantly different ( P = 0.019). Frequency of switching from either REM or W state was not significantly different. We conclude that sleep organization differs between lean and obese Zucker rats and that it is due to a disparity in switching from NREM sleep to either W or REM sleep and the mean duration of NREM sleep.

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.

scholarly journals Adipsin mRNA amounts are not decreased in the genetically obese Zucker rat

1989 ◽  
Vol 257 (3) ◽  
pp. 917-919 ◽  
Author(s):  
I Dugail ◽  
X Le Liepvre ◽  
A Quignard-Boulangé ◽  
J Pairault ◽  
M Lavau
Keyword(s):  
Gene Expression ◽  
High Fat Diet ◽  
Zucker Rats ◽  
Zucker Rat ◽  
Obese Mice ◽  
High Fat ◽  
Adult Rats ◽  
Obese Zucker Rat ◽  
Obese Rats ◽  
Obese Zucker Rats

Adipsin gene expression as assessed by mRNA amounts was examined in adipose tissue of genetically obese rats at the onset (16 days of age) or at later stages (30 and 60 days of age) of obesity. Amounts of mRNA were equivalent in obese and lean rats at 16 days of age. In adult rats, we observed a 2-fold decrease in adipsin mRNA in the obese rats compared with control lean rats, which was abolished by weaning the animals on a high-fat diet. Our data show that, in sharp contrast with genetically obese mice, adipsin mRNA is not suppressed in genetically obese Zucker rats.

Reduced renal responses to an acute saline load in obese Zucker rats

1991 ◽  
Vol 261 (3) ◽  
pp. R712-R718 ◽  
Author(s):  
D. W. Zeigler ◽  
K. P. Patel
Keyword(s):  
Blood Pressure ◽  
Sodium Excretion ◽  
Volume Expansion ◽  
Urine Flow ◽  
Reflex Response ◽  
Zucker Rats ◽  
Zucker Rat ◽  
Obese Zucker Rat ◽  
Obese Zucker Rats ◽  
Renal Responses

The purpose of this study was to determine if the reflex response to a saline load is altered in the obese Zucker rat. The obese Zucker rat is a genetic model of obesity and insulin-resistant diabetes that has been reported to have high blood pressure. We examined the reflux renal responses to volume expansion in both anesthetized obese and lean Zucker rats. Initial blood pressure was significantly elevated in the obese Zucker rats compared with the lean controls. Urine flow and sodium excretion from innervated and denervated kidneys were measured before and after volume expansion with normal saline. Volume expansion resulted in significantly less urine flow and sodium excretion in the obese than the lean Zucker rats. This response was evident in both the intact and denervated kidneys. Rats were then infused with atrial natriuretic peptide (ANP) to determine if natriuretic and diuretic responses were altered in these rats. The diuretic action of ANP was not significantly reduced in the obese Zucker rat. However, the natriuretic action of ANP was significantly attenuated in the obese rats. These results indicate that the reflux response to an acute saline load is attenuated in the obese Zucker rat and that this decreased response may be due to a reduction in the direct action of ANP on the kidney.

TNF-α acutely inhibits vascular effects of physiological but not high insulin or contraction

2003 ◽  
Vol 285 (3) ◽  
pp. E654-E660 ◽  
Author(s):  
Lei Zhang ◽  
Catherine M. Wheatley ◽  
Stephen M. Richards ◽  
Eugene J. Barrett ◽  
Michael G. Clark ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Muscle Contraction ◽  
Glucose Uptake ◽  
Capillary Flow ◽  
Insulin Dose ◽  
Whole Body ◽  
Vascular Effects ◽  
Capillary Recruitment ◽  
Tnf Α

TNF-α is elevated in many states of insulin resistance, and acutely administered TNF-α in vivo inhibits insulin-mediated hemodynamic effects and glucose uptake in muscle. In this study, we assess whether the inhibitory effects of TNF-α are affected by insulin dose or muscle contraction. Whole body glucose infusion rate (GIR), femoral blood flow (FBF), hindleg vascular resistance, hindleg glucose uptake (HGU), 2-deoxyglucose uptake into muscles of the lower leg (R′g) and hindleg metabolism of infused 1-methylxanthine (1-MX), a measure of capillary recruitment, were determined. Three groups were studied with and without infusion of TNF-α: euglycemic insulin-clamped, one-leg field-stimulated (2 Hz, 0.1 ms at 30 V), and saline-infused control anesthetized rats. Insulin infusions were 3, 10, or 30 mU · kg-1 · min-1 for 2 h. 1-MX metabolism was maximally increased by all three doses of insulin. GIR, HGU, and R′g were maximal at 10 mU and FBF was maximal at 30 mU of insulin. Contraction increased FBF, HGU, and 1-MX. TNF-α (0.5 μg · kg-1 · h-1) totally blocked the 3 and 10 mU insulin-mediated increases in FBF and 1-MX, and partly blocked GIR, HGU, and R′g. None of the increases due to twitch contraction was affected by TNF-α, and only the increase in FBF due to 30 mU of insulin was partly affected. We conclude that muscle capillary recruitment and glucose uptake due to high levels of insulin or muscle contraction under twitch stimuli at 2 Hz are resistant to TNF-α. These findings may have implications for ameliorating muscle insulin resistance resulting from increased plasma TNF-α and for the differing mechanisms by which contraction and insulin recruit capillary flow in muscle.

Pyruvate carboxylase in genetic obesity

1992 ◽  
Vol 262 (5) ◽  
pp. E608-E618 ◽  
Author(s):  
C. J. Lynch ◽  
K. M. McCall ◽  
M. L. Billingsley ◽  
L. M. Bohlen ◽  
S. P. Hreniuk ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Pyruvate Carboxylase ◽  
Zucker Rats ◽  
Zucker Rat ◽  
Rat Adipocytes ◽  
Obese Zucker Rat ◽  
Streptozotocin Induced Diabetes ◽  
Obese Zucker Rats ◽  
Relative Molecular Weight ◽  
Polyclonal Antisera

Immunoblotting and protein microsequencing were used to identify several adipocyte proteins expressed in an obesity-related fashion in the Zucker rat. One of these was a 116-kDa particulate protein (p116). The p116 levels in adipocytes from 5- to 7-wk-old obese Zucker rats were two- to fivefold higher on a per milligram of protein basis than levels in lean animals and decreased after the induction of streptozotocin-induced diabetes mellitus. This suggests the change may be related to the actions of insulin. Hepatic levels of p116 did not change. The p116 was purified to homogeneity from obese Zucker rat adipocytes, and polyclonal antisera were prepared against the purified protein in rabbits. Microanalysis of electroblotted p116 proteolytic fragments suggested that p116 was pyruvate carboxylase (PC). Other evidence that p116 was PC included the following: 1) p116 contained biotin, 2) p116 in particulate subcellular fractions was soluble after freeze-lysis, 3) antibodies to p116 reacted with purified hepatic PC, 4) p116 and purified hepatic PC had identical pI and relative molecular weight values, and 5) similar changes were detected in adipocyte p116 and PC enzyme activity during obesity and after the induction of streptozotocin-induced diabetes mellitus. Increased adipose tissue PC probably contributes to the increased lipogenic capacity of young obese Zucker rat adipocytes.

scholarly journals 2060 Exploring gene expression signature shared between obese Zucker rat and human cardiac hypertrophy

2018 ◽  
Vol 2 (S1) ◽  
pp. 11-11
Author(s):  
Mackenzie Newman ◽  
Janelle Stricker ◽  
Han-Gang Yu
Keyword(s):  
Cardiac Hypertrophy ◽  
Drug Target ◽  
Model Organism ◽  
Gene Expression Signature ◽  
Zucker Rats ◽  
Zucker Rat ◽  
Future Directions ◽  
Obese Zucker Rat ◽  
Study Population ◽  
Obese Zucker Rats

OBJECTIVES/SPECIFIC AIMS: Objectives: To determine genes that are shared between human and obese Zucker rat hypertrophic hearts, in order to identify potential early biomarkers and drug target for heart failure. METHODS/STUDY POPULATION: Four age-paired lean and obese Zucker rats were used. The human data are derived from doi:10.1152/physiolgenomics.00122.2016. RESULTS/ANTICIPATED RESULTS: We expect to find genes that are upregulated and downregulated in Zucker rats and humans that present cardiac hypertrophy. DISCUSSION/SIGNIFICANCE OF IMPACT: The genes and proteins determined from this study will provide future directions in order to determine whether obese Zucker rats are a valid model organism for the development of cardiac hypertrophy.

scholarly journals Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat

2010 ◽  
Vol 299 (3) ◽  
pp. G751-G760 ◽  
Author(s):  
Derek M. Culnan ◽  
Vance Albaugh ◽  
Mingjie Sun ◽  
Christopher J. Lynch ◽  
Charles H. Lang ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Zucker Rats ◽  
Ileal Interposition ◽  
Obese Zucker Rat ◽  
Obese Zucker Rats ◽  
Glucagon Like Peptide 1

The hindgut hypothesis posits improvements in Type 2 diabetes after gastric bypass surgery are due to enhanced delivery of undigested nutrients to the ileum, which increase incretin production and insulin sensitivity. The present study investigates the effect of ileal interposition (IT), surgically relocating a segment of distal ileum to the proximal jejunum, on glucose tolerance, insulin sensitivity, and glucose transport in the obese Zucker rat. Two groups of obese Zucker rats were studied: IT and sham surgery ad libitum fed (controls). Changes in food intake, body weight and composition, glucose tolerance, insulin sensitivity and tissue glucose uptake, and insulin signaling as well as plasma concentrations of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide were measured. The IT procedure did not significantly alter food intake, body weight, or composition. Obese Zucker rats demonstrated improved glucose tolerance 3 wk after IT compared with the control group ( P < 0.05). Euglycemic, hyperinsulinemic clamp and 1-[14C]-2-deoxyglucose tracer studies indicate that IT improves whole body glucose disposal, insulin-stimulated glucose uptake, and the ratio of phospho- to total Akt ( P < 0.01 vs. control) in striated muscle. After oral glucose, the plasma concentration of glucagon-like peptide-1 was increased, whereas GIP was decreased following IT. Enhanced nutrient delivery to the ileum after IT improves glucose tolerance, insulin sensitivity and muscle glucose uptake without altering food intake, body weight, or composition. These findings support the concept that anatomic and endocrine alterations in gut function play a role in the improvements in glucose homeostasis after the IT procedure.

Glucose uptake and GLUT-4 protein distribution in skeletal muscle of the obese Zucker rat

1994 ◽  
Vol 267 (1) ◽  
pp. R236-R243 ◽  
Author(s):  
J. T. Brozinick ◽  
G. J. Etgen ◽  
B. B. Yaspelkis ◽  
J. L. Ivy
Keyword(s):  
Plasma Membrane ◽  
Glucose Uptake ◽  
Protein Concentration ◽  
Protein Translocation ◽  
Zucker Rats ◽  
Zucker Rat ◽  
Protein Distribution ◽  
Glut 4 ◽  
Obese Zucker Rat ◽  
Obese Rats

The rates of muscle glucose uptake of lean and obese Zucker rats were assessed by hindlimb perfusion under basal conditions (no insulin), in the presence of a maximally stimulating concentration of insulin (10 mU/ml), and after muscle contraction elicited by electrical stimulation of the sciatic nerve. After perfusion, plasma and microsomal membranes were isolated from selected hindlimb muscles for determination of GLUT-4 protein distribution. Under basal conditions, rates of glucose uptake were similar for lean and obese rats despite plasma membranes from lean rats containing 82% more GLUT-4 protein than obese rats. Insulin stimulation resulted in significant increases in plasma membrane GLUT-4 protein concentration in lean but not obese rats. Glucose uptake of lean rats (35.3 +/- 4.7 mumol.h-1.g-1) in the presence of insulin was approximately fourfold greater than that of obese rats (8.8 +/- 1.3 mumol.h-1.g-1), but this difference in glucose uptake could not be completely accounted for by the difference in plasma membrane GLUT-4 protein concentration. Stimulation by contraction resulted in significant increases in plasma membrane GLUT-4 protein concentration in both lean and obese rats and similar rates of glucose uptake. These results suggest that the muscle insulin resistance of the obese Zucker rat is due to 1) a reduced plasma membrane GLUT-4 protein concentration, which results in part from an impairment in the insulin-stimulated GLUT-4 protein translocation process, and 2) a defect in the insulin-stimulated activation of this protein. However, contraction-stimulated glucose uptake, GLUT-4 protein translocation, and activation are normal in the obese Zucker rat.

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