Function In Obese Zucker Rats Research Articles

Renoprotection Induced by Aerobic Training Is Dependent on Nitric Oxide Bioavailability in Obese Zucker Rats.

Aerobic training (AT) promotes several health benefits that may attenuate the progression of obesity associated diabetes. Since AT is an important nitric oxide (NO−) inducer mediating kidney-healthy phenotype, the present study is aimed at investigating the effects of AT on metabolic parameters, morphological, redox balance, inflammatory profile, and vasoactive peptides in the kidney of obese-diabetic Zucker rats receiving L-NAME (N(omega)-nitro-L-arginine methyl ester). Forty male Zucker rats (6 wk old) were assigned into four groups (n = 10, each): sedentary lean rats (CTL-Lean), sedentary obese rats (CTL-Obese), AT trained obese rats without blocking nitric oxide synthase (NOS) (Obese+AT), and obese-trained with NOS block (Obese+AT+L-NAME). AT groups ran 60 min in the maximal lactate steady state (MLSS), five days/wk/8 wk. Obese+AT rats improved glycemic homeostasis, SBP, aerobic capacity, renal mitochondria integrity, redox balance, inflammatory profile (e.g., TNF-α, CRP, IL-10, IL-4, and IL-17a), and molecules related to renal NO− metabolism (klotho/FGF23 axis, vasoactive peptides, renal histology, and reduced proteinuria). However, none of these positive outcomes were observed in CTL-Obese and Obese+AT+L-NAME (p < 0.0001) groups. Although Obese+AT+L-NAME lowered BP (compared with CTL-Obese; p < 0.0001), renal damage was observed after AT intervention. Furthermore, AT training under conditions of low NO− concentration increased signaling pathways associated with ACE-2/ANG1-7/MASr. We conclude that AT represents an important nonpharmacological intervention to improve kidney function in obese Zucker rats. However, these renal and metabolic benefits promoted by AT are dependent on NO− bioavailability and its underlying regulatory mechanisms.

Mild Cognitive Impairment in the Presence of Depressive Symptoms Related to Impaired Cerebrovascular Function in the Obese Zucker Rat

Metabolic syndrome is a highly prevalent constellation of pathologies that frequently combines overweight/obesity, moderate hypertension, atherogenic dyslipidemia, and type II diabetes mellitus, and is accompanied by a systemic vascular pro‐inflammatory, pro‐oxidant condition. The evolution of metabolic syndrome is associated with elevated cerebrovascular disease risk including elevations in both the occurrence and the severity of stroke and transient ischemic attacks within the cerebral circulation. Frequently, these impairments to cerebral vascular function also result in cognitive and behavioral impairments to the afflicted individual even in the absence of an acute pathological event.Given the established elevation in depressive symptoms in OZR that develop in parallel to cerebrovascular dysfunction, we sought to determine the extent to which cognition was impaired.In this study 17–18‐wk‐old male lean and (LZR) obese Zucker rats (OZR) were tested for learning, memory, and behavioral flexibility using an operant conditioning chamber (OCC) and the Morris Water Maze (MWM). Learning was assessed by number of trials to reach 8 correct consecutive responses in OCC or a 6 trial MWM protocol. Performance in a retrieval or probe session 24 h after learning was used to measure memory in OCC and MWM respectively. Behavioral flexibility was measured by analyzing error types in OCC and search strategy in the MWM probe test. Depressive symptoms were measured using coat score, novelty suppressed feeding response, and latency to start grooming and frequency of subsequent grooming after sucrose spray. Ex vivo pressurized middle cerebral arteries (MCA) were used to determine the extent to which metabolic syndrome in OZR alters key indices of vascular reactivity of cerebral resistance vessels and the mechanics of the vascular wall.Endothelium dependent vasodilator reactivity was attenuated in OZR vs LZR in response to acetylcholine. Further impairments were demonstrated in OZR with an increase in depressive symptoms as measured by an increase in coat score and latency to start grooming after sucrose spray as well as mild cognitive impairment measured by increased time to reach the platform in MWM learning trials. In contrast, no signs of cognitive impairment were demonstrated in OCC. These results suggest that the changes in cerebrovascular function in OZR are associated with the development of depressive symptoms and mild cognitive impairment in MWM learning with no changes in learning, memory, or behavior flexibility in OCC at this age.Support or Funding InformationCIHR (#130138 and #389769); NSERC (RGPIN‐2018‐05450)

Sleeve Gastrectomy in Obese Zucker Rats Restores Cardiac Function and Geometry Toward a Lean Phenotype Independent of Weight Loss

Bariatric surgery, including sleeve gastrectomy (SG), significantly improves cardiac geometry and function in patients with heart failure. In this study, we used the obese Zucker rat as an animal model of heart failure with preserved ejection fraction (HFpEF) to test the hypothesis that a SG will improve cardiac function independent of weight loss. Obese, male Zucker rats underwent SG, pair-fed sham, or ad-lib sham surgery. Lean Zucker rats also underwent ad-lib sham surgery. Echocardiograms were performed preoperatively and at 6 weeks postoperatively. Obese SG and obese pair-fed sham rats had similar body weights postoperatively. Obese SG and lean, ad-lib, sham rats had a significant increase in postoperative stroke volume, and left ventricular internal diameter in diastole and systole. SG preserved systolic function and significantly improved isovolumetric relaxation time (13.9 ± 2.4 to 11.1 ± 2.1 ms, P = .02) independent of weight loss. SG has a beneficial impact on both systolic and diastolic cardiac function in obese Zucker rats toward a lean phenotype independent of weight loss and caloric restriction. These findings may represent a weight-loss independent mechanism generated from the gastrointestinal tract that has the potential to improve diastolic dysfunction independent of obesity status and translate to patients with HFpEF.

Early treatment with GLP-1 after severe trauma preserves renal function in obese Zucker rats.

Early posttrauma hyperglycemia (EPTH) is correlated with later adverse outcomes, including acute kidney injury (AKI). Controlling EPTH in the prehospital setting is difficult because of the variability in the ideal insulin dosage and the potential risk of hypoglycemia, especially in those with confounding medical comorbidities of obesity and insulin resistance. Glucagon-like peptide-1 (GLP-1) controls glucose levels in a glucose-dependent manner and is a current target in antidiabetic therapy. We have shown that after orthopedic trauma, obese Zucker rats exhibit EPTH and a later development of AKI (within 24 h). We hypothesized that GLP-1 treatment after trauma decreases EPTH and protects renal function in obese Zucker rats. Obese Zucker rats (~12 wk old) were fasted for 4 h before trauma. Soft tissue injury, fibula fracture, and homogenized bone component injection were then performed in both hind limbs to induce severe extremity trauma. Plasma glucose levels were measured before and 15, 30, 60, 120, 180, 240, and 300 min after trauma. GLP-1 (3 μg·kg-1·h-1, 1.5 ml/kg total) or saline was continuously infused from 30 min to 5 h after trauma. Afterwards, rats were placed in metabolic cages overnight for urine collection. The following day, plasma interleukin (IL)-6 levels, renal blood flow (RBF), glomerular filtration rate (GFR), and renal oxygen delivery (Do2) and consumption (V̇o2) were measured. EPTH was evident within 15 min after trauma but was significantly ameliorated during the 5 h of GLP-1 infusion. One day after trauma, plasma IL-6 was markedly increased in the trauma group and decreased in GLP-1-treated animals. RBF, GFR, and Do2 all significantly decreased with trauma, but renal V̇o2 was unchanged. GLP-1 treatment normalized RBF, GFR, and Do2 without affecting V̇o2. These results suggest that GLP-1 decreases EPTH and protects against a later development of AKI. Early treatment with GLP-1 (or its analogs) to rapidly, effectively, and safely control EPTH may be beneficial in the prehospital care of obese patients after trauma.

Early treatment with GLP-1 following severe trauma preserves renal function in obese Zucker rats

Early treatment with GLP-1 following severe trauma preserves renal function in obese Zucker rats

Altered post-capillary and collecting venular reactivity in skeletal muscle with metabolic syndrome.

With the development of the metabolic syndrome, both post-capillary and collecting venular dilator reactivity within the skeletal muscle of obese Zucker rats (OZR) is impaired. The impaired dilator reactivity in OZR reflects a loss in venular nitric oxide and PGI2 bioavailability, associated with the chronic elevation in oxidant stress. Additionally, with the impaired dilator responses, a modest increase in adrenergic constriction combined with an elevated thromboxane A2 production may contribute to impaired functional dilator and hyperaemic responses at the venular level. For the shift in skeletal muscle venular function with development of the metabolic syndrome, issues such as aggregate microvascular perfusion resistance, mass transport and exchange within with capillary networks, and fluid handling across the microcirculation are compelling avenues for future investigation. While research into vascular outcomes of the metabolic syndrome has focused on arterial/arteriolar and capillary levels, investigation into venular function and how this impacts responses has received little attention. Using the in situ cremaster muscle of obese Zucker rats (OZR; with lean Zucker rats (LZR) as controls), we determined indices of venular function. At ∼17weeks of age, skeletal muscle post-capillary venular density was reduced by ∼20% in LZR vs. OZR, although there was no evidence of remodelling of the venular wall. Venular tone at ∼25μm (post-capillary) and ∼75μm (collecting) diameter was elevated in OZR vs. LZR. Venular dilatation to acetylcholine was blunted in OZR vs. LZR due to increased oxidant stress-based loss of nitric oxide bioavailability (post-capillary) and increased α1 - (and α2 -) mediated constrictor tone (collecting). Venular constrictor responses in OZR were comparable to LZR for most stimuli, although constriction to α1 -adrenoreceptor stimulation was elevated. In response to field stimulation of the cremaster muscle (0.5, 1, 3Hz), venular dilator and hyperaemic responses to lower frequencies were blunted in OZR, but responses at 3Hz were similar between strains. Venous production of TxA2 was higher in OZR than LZR and significantly higher than PGI2 production in either following arachidonic acid challenge. These results suggest that multi-faceted alterations to skeletal muscle venular function in OZR may contribute to alterations in upstream capillary pressure profiles and the transcapillary exchange of solutes and water under conditions of metabolic syndrome.

Induction of Heme Oxygenase with Hemin Improves Impaired Insulin Signaling and Compromised Cardiac Structure and Function in Obese Zucker Rats

BackgroundDiabetic cardiomyopathy is characterized by cardiac dysfunction and impaired insulin signaling. The mechanisms that drive obesity and insulin‐resistant mediated cardiomyopathy are not completely elucidated. Accordingly, the aim of this study was to examine the effects of upregulating the heme‐oxygenase (HO) on obesity related cardiac dysfunction and impaired insulin signaling in obese Zucker rats, a model characterized by insulin resistance and cardiomyopathy.MethodsImmunohistochemistry, spectrophotometry, enzyme‐linked immunosorbent assay (ELISA) and Western blotting were used. In addition non‐invasive echocardiography and invasive left ventricular (LV) cannulation was employed to evaluate the hemodynamic, echocardiographic and electrophysiological parameters of the myocardium. HO was enhanced with hemin or blocked with stannous mesoporphyrin.ResultsOur data demonstrated that administering hemin to obese Zucker rats; (i) enhanced important proteins of insulin signaling (IRS‐1, PI3K and GLUT4), (ii) reduced glucose intolerance, (iii) suppressed HOMA‐index, but (iv) increased adiponectin and atrial‐natriuretic‐peptide (ANP). Interestingly, the improvement of insulin sensitivity and glucose metabolism was accompanied by attenuation of cardiomyocytes longitudinal muscle‐fiber thickness, the reduction of diastolic/systolic free‐wall thickness and the suppression of LV hypertrophy. Furthermore, hemin attenuated inflammation/oxidative stress, suppressed fibrosis, extracellular matrix/pro‐fibrotic proteins (collagen‐IV, fibronectin, TGF‐β1) as well as proteins of heart failure such as osteopontin and osteoprotegerin. These were associated with improved cardiac function as evidenced by improved hemodynamics such as mean‐arterial pressure, arterial‐systolic pressure, +dP/dt, arterial‐diastolic pressure and improved electrocardiographic parameters associated with cardiac conduction system including PR‐interval, QRS‐duration, ST‐segment and QT interval. However, the HO blocker, stannous‐mesoporphyrin reversed the cardio‐protective effects of hemin.ConclusionOur findings demonstrates that hemin improved compromised cardiac structure and function in obese Zucker rats. Interestingly, attenuation of inflammation, oxidative stress, extracellular‐matrix/profibrotic proteins, cardiac hypertrophy and fibrosis alongside the potentiation of adiponectin, ANP and proteins of insulin signaling are among the multifaceted mechanisms through which an upregulated HO‐system improves insulin sensitivity, glucose metabolism and diabetic cardiomyopathy. Thus, HO‐inducers may be explored as a novel therapy for diabetic cardiomyopathy.Support or Funding InformationHeart &amp; Stroke Foundation of Saskatchewan, Canada

Treatment with Losartan Improves Baroreflexes in Obese Zucker Rats Coincident with Enhanced Response of Nucleus Tractus Solitarius (NTS) to Increased Arterial Pressure

Obese Zucker rats (OZR) have impaired baroreflex‐mediated responses to acute rises in mean arterial pressure (MAP) coincident with the development of hypertension. In addition, the NTS becomes less responsive, with reduced phenylephrine (PE)‐induced c‐Fos expression and smaller physiological responses to glutamate in the NTS. Here, we determined if treatment with the angiotensin‐ AT1 receptor antagonist, losartan (LOS) improves baroreflexes and the PE‐induced c‐Fos expression in NTS of OZR. Baroreflex‐mediated changes in HR to PE‐evoked rises in MAP (40 mmHg) were measured in conscious rats implanted with femoral catheters. Rises in MAP were sustained with PE, and then rats were perfused after 90 min to examine NTS c‐Fos expression. Treatment with LOS (for 5 wks) normalized MAP in OZR vs. LZR (untreated: 128±2 vs. 115±3 mmHg, with LOS: 111±3 vs. 112±2 mmHg; at 14.1 wks). LOS treatment enhanced PE‐induced reductions in HR in OZR but not LZR. (untreated: 43±10 vs. ‐101±9 ‐bpm; with LOS:. ‐75±12 vs. ‐112±11bpm). Although LOS improved PE‐induced reductions in HR in OZR, responses in LOS‐treated OZR were still smaller vs. LOS‐treated LZR, suggesting a partial restoration of baroreflexes. PE‐induced c‐Fos expression in NTS was less in untreated OZR vs. LZR (30±5 vs. 50±6 counts). Treatment with LOS enhanced PE‐induced c‐Fos expression in OZR (54±11 counts), but not LZR (58±11 counts), rendering comparable PE‐induced c‐Fos expression in LOS‐treated OZR and LZR. These data suggest that LOS improves hypertension, baroreflexes, and NTS function in OZR. Further study is needed to determine whether improved function by LOS is explained by normalization of MAP in OZR. Support: AHA GRNT18880005.

Featured article: induction of heme oxygenase with hemin improves pericardial adipocyte morphology and function in obese Zucker rats by enhancing proteins of regeneration.

Oxidative stress and inflammation are implicated in tissue remodeling, hypertrophy, and organ malfunction. Since heme-oxygenase (HO) is a cytoprotective enzyme with effects against oxidative stress and inflammation, we investigated the effects of upregulating HO with hemin on adipocyte hypertrophy, proteins of repair/regeneration including beta-catenin, Oct3/4 and Pax2 as well as pro-fibrotic/remodeling proteins like osteopontin and transforming growth factor-beta (TGF-β) in pericardial adipose tissue from obese Zucker rats (ZRs). Treatment with hemin significantly reduced pericardial adipose tissue inflammation/oxidative stress, suppressed osteopontin and TGF-β, and attenuated pericardial adipocyte hypertrophy in obese ZRs. These were associated with enhanced expression of the stem/progenitor-cell marker cKit; the potentiation of several proteins of regeneration including beta-catenin, Oct3/4, Pax2; and improved pericardial adipocyte morphology. Interestingly, the amelioration of adipocyte hypertrophy in hemin-treated animals was accompanied by improved adipocyte function, evidenced by increased levels of pericardial adipose tissue adiponectin. Furthermore, hemin significantly reduced hypertriglyceridemia and hypercholesteromia in obese ZRs. The protective effects of hemin were accompanied by robust potentiation HO activity and the total antioxidant capacity, whereas the co-administration of hemin with the HO inhibitor, stannous mesoporphyrin abolished the effects of hemin. These data suggest that hemin improves pericardial adipocyte morphology and function by enhancing proteins of repair and regeneration, while concomitantly abating inflammatory/oxidative insults and suppressing extracellular-matrix/profibrotic and remodeling proteins. The reduction of hypertriglyceridemia, hypercholesteromia, pericardial adiposity, and pericardial adipocyte hypertrophy with corresponding improvement of adipocyte morphology/function in hemin-treated animals suggests that HO inducers may be explored for the design of novel remedies against cardiac complications arising from excessive adiposity.

Cross‐talk between NAD(P)H oxidase and AT1 receptors in the proximal tubules of obese Zucker rats

Abnormal regulation of renin‐angiotensin system and increased level of oxidative stress have been implicated in renal/cardiovascular diseases associated with obesity. Earlier, we have shown that Angiotensin II AT1 receptor activity causes greater antinatriuresis via enhanced stimulation of tubular Na,K‐ATPase (NKA) in obese Zucker rats. The present study investigated the role of NAD(P)H oxidase in the enhanced AT1 receptor function in obese Zucker rats. Lean and obese Zucker rats were given NAD(P)H oxidase inhibitor, apocynin (3.5 μg/kg/min; i.v infusion) and/or AT1 receptor antagonist, candesartan (100 μg/kg; i.v bolus). Pretreatment with apocynin completely abolished candesartan‐induced diuresis/natriuresis in obese Zucker rats. In lean Zucker rats, apocynin alone increased diuresis/natriuresis and had an additive effect on diuresis/natriuresis when given along with candesartan. The blood pressure and GFR remained unchanged during drug treatment indicating a tubular effect. Apocynin treatment abolished and brought the AngII‐stimulated NKA activity below the basal activity in the isolated proximal tubules of obese Zucker rats. The data suggest NAD(P)H oxidase as an antinatriuretic molecule that switches to AT1 receptor signaling in the proximal tubules of obese Zucker rats and thereby contributes to the enhanced antinatriuresis. (NIH‐R01‐DK‐61578; GEAR‐UH)

Abstract 1137: Switch From Nitric Oxide To Hydrogen Peroxide Mediated Dilation In Coronary Arterioles Of Obese Rats

Background. Obesity is associated with coronary endothelial dysfunction, an early marker of atherosclerosis; but impaired endothelial function in obese Zucker rats appears not to be mediated by NO production. Hypothesis: We tested the hypothesis that endothelial derived hyperpolarizing factor (EDHF) is responsible for endothelial dilation in obese rats. Methods: We used 4 groups of male Zucker rats: lean and obese on normal and low carb diets. Rats were fed ad libitum for 3 weeks; caloric intake and weight gain were similar. Coronary arterioles were cannulated and pressurized for diameter measurements. Vasodilation to acetylcholine (Ach) and flow was determined before and after incubation with L-NAME (10 μm), an inhibitor of NO synthase, plus the cyclooxygenase inhibitor indomethacin (Indo; 10 μm), after tetraethylammonium (TEA 1 mM), a non-selective K + channel antagonist, and after catalase, a H 2 O 2 scavenger (CAT; 500 U/ml). Results Acetylcholine-induced vasodilation was impaired in obese rats compared to lean (41%; n=5 vs 87%; n=3; p&lt;0.05) and did not change after L-NAME+Indo incubation in obese both on normal (47 ± 19%; n = 4 vs . 40 ± 13%; n = 4; p =ns) and low carb diet (51 ± 1%; n = 3 vs . 59 ± 6%; n = 3; p =ns). Flow-induced dilation was impaired in obese rats compared to lean (38%;n=5 vs 78%; n=2;p&lt;0.05) and this dilation was not affected by L-NAME+Indo incubation in obese both on normal (45±12%; n=4 vs 48±10% n=4; p =ns) and low carb diet (53±14%; n=3 vs 61±12% n=3; p =ns). Importantly, TEA incubation decreased Ach dilation both in obese on normal (41±11%; n=5 vs 13±7% n=5; p&lt; 0.05) and low carb diet (76±25%; n=3 vs 22±18% n=3; p&lt; 0.05). Similar results were obtained during flow-induced dilation in obese both on normal (37±17%; n=5 vs 14±7% n=5; p&lt; 0.05) and low carb diet (54±14%; n=3 vs 15±3% n=3; p&lt; 0.05). Catalase administration blocked both FID and Ach dilation in obese both on normal (FID 45±15% vs 5±3% n=3; p&lt; 0.05; Ach 39±14% vs 12±5% n=3; p&lt;0.05) and low carb diet (FID 52±19% vs 18±7% n=2; p&lt; 0.05; Ach 75±35% vs 15±2% n=2; p&lt; 0.05). Conclusions: Endothelial dependent vasodilation of coronary arterioles in obese Zucker rats is mediated by H 2 O 2 and increases in endothelial function in obese rats on a low carb diet is mediated by increased H 2 O 2 -induced dilation.

The influence of pomegranate fruit extract in comparison to regular pomegranate juice and seed oil on nitric oxide and arterial function in obese Zucker rats

Metabolic syndrome includes most widely distributed clinical conditions such as obesity, hypertension, dislipidemia, and diabetes. Pomegranate fruit extract (PFE), rich in polyphenolic antioxidants, reduces the expression of oxidation-sensitive genes at the sites of perturbed shear-stress. The aim of this study was to evaluate the effect of PFE in comparison to regular pomegranate juice (PJ) and seed oil on the biological actions of nitric oxide (NO) and the arterial function in obese Zucker rats, a model of metabolic syndrome. Our results indicated that supplementation with PFE or PJ significantly decreased the expression of vascular inflammation markers, thrombospondin (TSP), and cytokine TGFβ1 ( P < 0.05), whereas seed oil supplementation had a significant effect only on TSP-1 expression ( P < 0.05). Plasma nitrate and nitrite (NO x ) levels were significantly increased by PFE and PJ ( P < 0.05). Furthermore, the effect of PFE in increasing endothelial NO synthase (eNOS) expression was comparable to that of PJ. These data highlight possible clinical applications of PFE in metabolic syndrome.

Metabolic Syndrome

Metabolic Syndrome

Restoration of coronary endothelial function in obese Zucker rats by a low-carbohydrate diet

A popular diet used for weight reduction is the low-carbohydrate diet, which has most calories derived from fat and protein, but effects of this dietary regimen on coronary vascular function have not been identified. We tested the hypothesis that obesity-induced impairment in coronary endothelial function is reversed by a low-carbohydrate diet. We used four groups of male Zucker rats: lean and obese on normal and low-carbohydrate diets. Rats were fed ad libitum for 3 wk; total caloric intake and weight gain were similar in both diets. To assess endothelial and vascular function, coronary arterioles were cannulated and pressurized for diameter measurements during administration of acetylcholine or sodium nitroprusside or during flow. When compared with lean rats, endothelium-dependent acetylcholine-induced vasodilation was impaired by approximately 50% in obese rats (normal diet), but it was restored to normal by the low-carbohydrate diet. When the normal diet was fed, flow-induced dilation (FID) was impaired by >50% in obese compared with lean rats. Similar to acetylcholine, responses to FID were restored to normal by a low-carbohydrate diet. N(omega)-nitro-L-arginine methyl ester (10 microM), an inhibitor of nitric oxide (NO) synthase, inhibited acetylcholine- and flow-induced dilation in lean rats, but it had no effect on acetylcholine- or flow-induced vasodilation in obese rats on a low-carbohydrate diet. Tetraethylammonium, a nonspecific K(+) channel antagonist, blocked flow-dependent dilation in the obese rats, suggesting that the improvement in function was mediated by a hyperpolarizing factor independent of NO. In conclusion, obesity-induced impairment in endothelium-dependent vasodilation of coronary arterioles can be dramatically improved with a low-carbohydrate diet most likely through the production of a hyperpolarizing factor independent of NO.

PPAR-α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats

Previous studies have shown that the synthesis of renal cytochrome P-450 (CYP)-derived eicosanoids is downregulated in genetic or high-fat diet-induced obese rats. Experiments were designed to determine whether fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg.kg(-1).day(-1) for 4 wk) significantly reduced plasma insulin, triglyceride, and total cholesterol levels in obese Zucker rats. CYP2C11 and CYP2C23 proteins were downregulated in renal vessels of obese Zucker rats. Consequently, renal vascular epoxygenase activity decreased by 15% in obese Zucker rats compared with lean controls. Chronic fenofibrate treatment significantly increased renal cortical and vascular CYP2C11 and CYP2C23 protein levels in obese Zucker rats, whereas it had no effect on epoxygenase protein and activity in lean Zucker rats. Renal cortical and vascular epoxygenase activities were consequently increased by 54% and 18%, respectively, in fenofibrate-treated obese rats. In addition, acetylcholine (1 microM)-induced vasodilation was significantly reduced in obese Zucker kidneys (37% +/- 11%) compared with lean controls (67% +/- 9%). Chronic fenofibrate administration increased afferent arteriolar responses to 1 microM of acetylcholine in obese Zucker rats (69% +/- 4%). Inhibition of the epoxygenase pathway with 6-(2-propargyloxyphenyl)hexanoic acid attenuated afferent arteriolar diameter responses to acetylcholine to a greater extent in lean compared with obese Zucker rats. These results demonstrate that the PPAR-alpha agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.

Exercise-induced increase in skeletal muscle vasodilatory responses in obese Zucker rats

The purpose of this study was to test the hypothesis that exercise training improves microvascular function in obese Zucker rats, a model of obesity and type II diabetes. Animals were divided into four age-matched groups: lean sedentary (LS), lean exercise (LE), obese sedentary (OS), and obese exercise (OE). The exercise groups were treadmill-exercised from 5 to 11 wk of age, including a 2-wk acclimation period. Mean arterial pressure (MAP) was not significantly different between any of the groups. The OS had significantly higher mean body weight, blood glucose, insulin, IL-6, and leptin levels compared with the LS, whereas the OE had significantly lower blood glucose, insulin, and IL-6 levels compared with the OS. Functional hyperemia and endothelial-dependent vasodilation were tested in the spinotrapezius muscle using intravital microscopy. Functional hyperemia and acetylcholine (0.1 microM, 1 microM, and 10 microM) responses were significantly attenuated in OS compared with the LS, while the contraction and ACh-induced (1 microM and 10 microM) vasodilation were significantly increased in both LE and OE compared with the sedentary animals. These results suggest that exercise training can improve vascular function in this model of type II diabetes. Moreover, the impaired vasodilation observed in 11-wk-old OZR suggests that the microvascular dysfunction is not likely due to an elevated blood pressure.

Renal dopamine D1receptor dysfunction is acquired and not inherited in obese Zucker rats

In essential hypertension, the defect in renal dopamine (DA) D(1) receptor function is intrinsic to proximal tubules as this phenomenon is also seen in primary proximal tubule cultures from spontaneously hypertensive rats (SHR) and essential hypertensive patients. Previously, a defect was reported in renal D(1) receptor function in obese Zucker rats. In the present study, we sought to determine whether this D(1) receptor dysfunction is intrinsic in these animals. In primary proximal tubular epithelial cells (PTECs) from lean and obese rats, DA inhibited Na-K-ATPase (NKA) activity in PTECs from both groups of rats. Basal NKA activity, D(1) receptor protein expression, and their coupling to G proteins were similar in cells from both groups. However, when PTECs from lean and obese rats were cultured in 20% serum from obese rats, DA failed to inhibit NKA activity, which was accompanied by a reduction in D(1) receptor expression and a defect in D(1) receptor-G protein coupling. No such defects in the inhibitory effect of DA on NKA activity, D(1) receptor numbers, or coupling were seen when PTECs from both lean and obese rats were grown in 20% serum from lean or rosiglitazone-treated obese (RTO) rats. RTO rat serum had normal blood glucose and reduced plasma levels of insulin compared with serum from obese rats. Furthermore, chronic insulin treatment of PTECs from lean and obese rats caused an attenuation in DA-induced NKA inhibition, a decrease in D(1) receptor expression, and D(1) receptor-G protein uncoupling. These results suggest that defective D(1) receptor function in obese Zucker rats is not inherited but contributed to by hyperinsulinemia and/or other circulating factors associated with obesity.

Rosiglitazone Treatment Restores Renal Dopamine Receptor Function in Obese Zucker Rats

Earlier we have reported a defective dopamine D1-like receptor function, which was accompanied by a decrease in D1 receptor numbers and the inability of dopamine to inhibit Na,K-ATPase and Na,H-exchanger in proximal tubules of hyperinsulinemic obese Zucker rats. The present study was designed to test the hypothesis that the defect in dopamine receptor function is a result of hyperinsulinemia in obese rats. We designed experiments to study D1 receptor function in obese Zucker rats treated with rosiglitazone, as it lowers plasma insulin by improving insulin sensitivity. A group of untreated lean and obese rats served as controls. Rosiglitazone treatment (10 mg/kg orally, 4 weeks) caused significant decreases in plasma insulin, blood glucose, and blood pressure while causing an increase in renal sodium excretion compared with untreated obese rats. In the isolated proximal tubules obtained from untreated lean rats, dopamine caused concentration-dependent inhibition of the Na,K-ATPase activity, but this inhibitory effect was absent in untreated obese rats. In rosiglitazone-treated obese rats, the inhibitory effect of dopamine on Na,K-ATPase was significantly restored. This was accompanied by a complete restoration of D1 receptor numbers in proximal tubular membranes of treated obese rats. In another set of experiments, treatment of primary proximal tubule epithelial cells in culture medium with insulin caused a significant decrease in the D1 receptor abundance, suggesting a direct role of insulin on D1 receptor regulation. We conclude that hyperinsulinemia causes downregulation of D1 receptor function and lowering of plasma insulin levels leads to restoration of renal D1 receptor function.