The Zucker fatty rat as a genetic model of obesity and hypertension.

Kurtz, Theodore W.; Morris, R. Curtis; Pershadsingh, Harrihar A.

doi:10.1161/01.hyp.13.6.896

Cited by 233 publications

(156 citation statements)

References 24 publications

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“…Although renal hemodynamics are often critical in the rate of progression of renal disease, we consider this to be an unlikely explanation for the salutary effect of pair-feeding in OZRs. Transglomerular capillary pressures are not markedly elevated in proteinuric OZRs (35,36), pair-feeding has not been shown to reduce blood pressure (37), and reduction of blood pressure in OZRs with pharmacological agents does not uniformly lead to reduction in renal disease (38). Protein restriction reduces the progression of renal disease pathology in rats, but caloric restriction without protein restriction accomplishes the same effect (39,40).…”

Section: Discussionmentioning

confidence: 99%

Hyperphagia as a Mediator of Renal Disease Initiation in Obese Zucker Rats

et al. 2001

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Objective: We sought to determine whether prevention of overeating would block the very earliest manifestations of renal injury in young obese Zucker rats (OZRs). Research Methods and Procedures: Three groups of rats were studied, obese (fa/fa) Zucker rats and lean (Fa/Fa). Zucker controls were allowed to feed ad libitum, whereas a group of obese (fa/fa) Zucker rats was pair-fed to the lean group. Urine albumin and serum lipids were studied weekly from 6 to 10 weeks of age. Renal pathology and renal glomerular gene expression were examined when the rats were killed at 10 weeks of age. Results: Obese rats fed ad libitum developed significant albuminuria by 6 weeks of age, increasing at each subsequent time-point. This increase was completely blocked by pair-feeding. Serum triglycerides were significantly increased in obese rats fed ad libitum vs. the other groups. Urine albumin correlated significantly with both body weight and serum triglyceride level. Renal histopathology was normal in all groups. Analysis of gene expression of glomerular proteins by reverse transcriptase-polymerase chain reaction revealed that pair-feeding attenuated the increased expression of glomerular desmin, fibronectin, and the 92-kDa collagenase that was seen in obese animals fed ad libitum. Discussion: Prevention of overeating in young OZR normalizes albuminuria and attenuates the pathogenic alterations in glomerular gene expression seen at the initiation of renal disease in obese animals allowed to feed ad libitum. This model may be relevant for studying the early endorgan effects of obesity.

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Section: Discussionmentioning

confidence: 99%

Hyperphagia as a Mediator of Renal Disease Initiation in Obese Zucker Rats

et al. 2001

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“…The rats have been maintained on the SHR background, which explains their severe hypertension. Furthermore, obese Zucker fatty rats (fa/fa rats) with leptin receptor mutations (17,58) exhibit marked BP elevation (59). In Zucker fatty rats, increased BP appears to be associated with the obese genotype (59).…”

Section: Figurementioning

confidence: 99%

Pathophysiological role of leptin in obesity-related hypertension

Aizawa-Abe¹,

Ogawa²,

Masuzaki³

et al. 2000

J. Clin. Invest.

434

312

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IntroductionObesity is defined as increased mass of adipose tissue and confers a higher risk of arterial blood pressure (BP) elevation or hypertension (1-4). On the other hand, weight reduction lowers BP in obese hypertensive subjects (5-8), suggesting an important association between energy homeostasis and BP. However, the mechanism for that association is poorly understood. Obesity-related hypertension may be secondary to insulin resistance and/or hyperinsulinemia (2,3,8). Several lines of evidence have also suggested that increased sympathetic nerve activity may contribute to the development of obesity-related hypertension (2, 6, 7).The adipose tissue participates in the regulation of a variety of homeostatic processes as an endocrine organ that secretes many biologically active molecules such as FFA, adipsin, angiotensinogen,. Leptin is such an adipocyte-derived hormone that is involved in the regulation of food intake and body weight (10). It also increases the overall sympathetic nerve activity, which leads to a significant increase in energy expenditure (11-15). The biologic actions of leptin are thought to be mediated through the activation of leptin receptor that is expressed in the hypothalamus (16)(17)(18)(19). We and others demonstrated that the hypothalamic arcuate nucleus is a primary site of the satiety effect of leptin (20,21) and that its satiety effect is mediated at least partly by hypothalamic melanocortin system (22,23).Numerous studies have demonstrated that plasma leptin concentrations are elevated significantly in several models of rodent obesity and in human obesity in proportion to the degree of adiposity (24-26), suggesting the state of "leptin resistance" in obesity. Nevertheless, because of the potent pleiotropic actions of leptin, it is conceivable, though paradoxically, that hyperleptinemia may be involved in the pathogenesis of obesity and its related disorders. In this regard, a recent study reported a significant correlation between BP and plasma leptin concentrations in patients with essential hypertension (27), suggesting that leptin may play roles in the pathogenesis of obesity-related hypertension.We have recently produced transgenic skinny mice overexpressing leptin under the control of the liver-specific promoter and demonstrated that chronic hyperleptinemia results in complete disappearance of adipose tissue for a long period (28). These mice also exhibit increased glucose metabolism and insulin sensitivity, accompanied by an activation of insulin signaling in the skeletal muscle and liver (28,29). Accordingly, transgenic skinny mice will serve as the unique experimental model system with which to assess the long-term effects of leptin in vivo. To explore the pathophysiological role of leptin in obesity-related hypertension, we examined cardiovascular phenotypes of transgenic skinny mice whose elevated plasma leptin concentrations are comparable to those seen in obese subjects. We also studied genetically obese KKA y mice with hyperleptinemia, in which hypothalamic melano...

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“…Support for this supposition comes from reports that obese Zucker rats, fed ad libitum throughout life, become hypertensive by approximately 36 weeks of age. 20,21 Speci®cally, it is documented that resting heart rates in adult obese Zucker rats are approx 400 bpm (approx 13% higher than lean litter mates) and systolic arterial blood pressures are approx 130 mmHg (approx 15% higher than lean litter mates). 20,21 It follows that this obesity-related increase in resting heart rate and systolic blood pressure would elevate the rate pressure product and therefore, increase myocardial oxygen consumption.…”

Section: Obesity and Myocardial Lipid Peroxidationmentioning

confidence: 99%

Obesity is associated with increased myocardial oxidative stress

et al. 1999

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OBJECTIVE: To determine: 1) whether obesity predisposes the myocardium to oxidative stress as evidenced by higher tissue levels of myocardial lipid peroxidation, and 2) what cellular mechanisms are responsible for this predisposition. DESIGN: Comparative, descriptive study of the myocardial tissue of lean and obese Fatty Zucker animals. ANIMALS: 12 month old lean ( 7 afa; n 6; mean body weight 590 g) and obese (faafa; na 7; mean body weight 882 g) male Fatty Zucker rats. MEASUREMENTS: Basal lipid peroxidation (assessed using thiobarbituric reactive acid substances (TBARS) and cumene hydroperoxide equivalents), oxidative and antioxidant enzyme activities (citrate synthase (CS), superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT), thiol content, heat shock protein expression (HSP72a73) and TBARS concentrations following an iron-mediated challenge in vitro. RESULTS: Compared to lean, lipid peroxidation was greater (P`0.05) in the left ventricle (LV) from obese rats as indicated by higher levels of lipid hydroperoxides (mean 11.48 vs 13.7 cumene hydroperoxide equivalents (CHPE)amg lipid) and TBARS (mean 11.1 vs 13.9 nMolamg lipid.). The activity of the manganese isoform of superoxide dismutase in the LV was higher (P`0.05) in obese animals, compared to controls (mean 135 vs 117 Uamg protein). In contrast, LV catalase and glutathione peroxidase activities did not differ (P b 0.05) between groups. Also, LV levels of HSP 72 (inducible) and 73 (constitutive) did not differ (P b 0.05)( between lean and obese animals. Following an iron-stimulated oxidative challenge in vitro, TBARS concentration was signi®cantly greater (P`0.05) in LV of obese rats compared to the lean (mean 12.7 vs 16.7 nMolamg lipid). CONCLUSIONS: These results support the notion that obesity predisposes the myocardium to oxidative stress. However, the postulate that obesity is associated with elevated myocardial antioxidant enzyme activities and HSPs was only partially supported by these ®ndings.

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The Zucker fatty rat as a genetic model of obesity and hypertension.

Cited by 233 publications

References 24 publications

Hyperphagia as a Mediator of Renal Disease Initiation in Obese Zucker Rats

Hyperphagia as a Mediator of Renal Disease Initiation in Obese Zucker Rats

Pathophysiological role of leptin in obesity-related hypertension

Obesity is associated with increased myocardial oxidative stress

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