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Zucker fatty rats have a mutated leptin receptor Phillips et al. They are hyperinsulinemic Trimble et al. The Zucker diabetic fatty ZDF rat is a substrain of the Zucker fatty rat, which was derived from hyperglycemic Zucker fatty rats to gain a model with diabetic features Peterson et al.
It is severely insulin resistant and males become overtly diabetic at 8—10 weeks, which is due to an inability of beta cells to compensate for insulin resistance, which is associated with changes in islet morphology Tokuyama et al.
Females do not tend to develop overt diabetes but diabetes can be induced by feeding a high-fat diet Corsetti et al. Boegehold, in Comprehensive Toxicology The fa mutation is an autosomal recessive locus on chromosome 5, and homogeneity in an improperly coded leptin receptor gene Baron et al. Owing to this mutation, OZRs experience an impaired satiety reflex and chronic hyperphagia, with rapid development of profound obesity and many of the other comorbidities associated with excess adiposity, including impaired glycemic control and profound hypertriglyceridemia Bray Additionally, OZRs ultimately develop a moderate, clinically relevant hypertension Frisbee a; Toblli et al.
More recent study has demonstrated that OZRs also exist in a profound proinflammatory and prothrombotic Vaziri et al. As development of the metabolic syndrome in OZR stems from a chronic elevation in caloric intake, this model can be highly relevant for investigation of Species fatties mature evolution of the metabolic syndrome in humans.
In addition, OZRs experience a prolonged period of hypertriglyceridemia and insulin resistance prior to the onset of overt development of type II diabetes mellitus, as is frequently the case in obese humans, and the degree of hypertension that does develop in OZR can best be described as mild to moderate, which is also in keeping with the elevations in arterial pressure identified in many people afflicted with the metabolic syndrome. Finally, the recent identification of a proinflammatory and prothrombotic environment within OZR has also demonstrated consistent parallels to conditions of the metabolic syndrome in humans.
At rest, skeletal muscle arteriolar perfusion in OZR has been demonstrated to be reduced as compared to levels determined in LZR, and this has been observed in both cremaster Frisbee and Stepp and spinotrapezius muscle preparations Xiang et al. Additionally, limited evidence suggests that the total perfusion response during reactive hyperemia in skeletal muscle of OZR is reduced in obese animals relative to that in controls Frisbee Investigation into active hyperemia suggests that the ability of the skeletal muscle circulation of OZR to provide for adequate convective and diffusive substrate delivery during elevated metabolic demand may be compromised versus LZR.
Ongoing studies using in situ gastrocnemius muscle have demonstrated that this constrained active hyperemia is also evident for bulk perfusion to skeletal muscle Frisbee from these studies suggest that impaired active hyperemia within skeletal muscle of OZR may be present regardless of metabolic demand severity. Yorek, in International Review of Neurobiology Obese Zucker rats do not become hyperglycemic, but are hyperlipemic, hypercholesterolemic, hyperinsulinemic, and develop adipocyte hypertrophy and hyperplasia Alderson et al.
The Species fatties mature rat has also occasionally been used in investigations of obesity-associated noninsulin-dependent diabetes mellitus. In our studies with this model, we found that vascular and neural dysfunction developed at a slower rate in obese Zucker rats than in the Zucker diabetic fatty ZDF rat model of type 2 diabetes see later. In both models, vascular impairment preceded slowing of motor nerve conduction velocity, which occurs at 12—14 weeks of age in ZDF rats and 32 weeks of age in obese Zucker rats Oltman et al.
Dwight R. The Zucker obese rat is outbred and multicolored, with four principal coat colors: 1 predominantly brown, 2 brown and white, 3 predominantly black, and 4 black and white. The first rat model of genetic obesity was described by Zucker and Zucker, ; Zucker and Antoniades, The Zucker rat was developed from crosses between animals from the Sherman strain and the Merck stock 13 M strain Kava et al.
The mutation was determined to be a shortened leptin-receptor protein resulting from a single nucleotide substitution at position of the leptin-receptor gene Chua et al. This obese rat model is characterized by hyperlipidemia, hypercholesterolemia, and hyperinsulinemia and develops adipocyte hypertrophy and hyperplasia.
It has been a valuable contributor to the study of early-onset hyperplastichypertrophic obesity. Although the obese Zucker rat is hyperphagic compared with its lean Species fatties mature, the hyperphagia is not necessary for expression of the obesity syndrome. A study by Greenwood et al.
Some data suggest that the obese Zucker has a profoundly abnormal brain neuropeptide physiology and that this abnormality may show a fa gene-dose effect Baskin et al. Furthermore, this rat is hyperinsulinemic, hypertriglyceridemic, and non-hypertensive, making it useful for studies of the pre-diabetic state. Geiger, E. Pothos, in Handbook of Behavioral Neuroscience The fa genotype is a missense mutation on the leptin receptor gene that renders the gene nonfunctional. In addition to the traditional Zucker fatty rat, it has been further selectively bred for hyperglycemia to produce a diabetic rat model referred to as the Zucker diabetic fatty ZDF rat Bray, ; Wang et al.
When investigating the links between obesity, impaired leptin aling, and dopamine, the Zucker rat was used to show that bromocriptine, a dopamine D2 receptor agonist, could be used to decrease food intake and body fat and increase locomotor activity in these animals Davis et al. Julie C. Paul J. The Zucker fatty rat is used as a model of human obesity accompanied with hyperlipidemia and hypertension. Inbreeding of the Zucker fatty rat for hyperglycemia gave rise to the ZDF rat strain, which are less obese than the Zucker fatty rat, but have more severe insulin resistance Pick et al.
Diabetes develops in males at 8 weeks of age, but females do not develop overt diabetes Peterson et al. At the biochemical level, lenses of the ZDF rats exhibited 3-fold increase in glucose and fructose, and a fold increase in sorbitol levels McCaleb and Sredy,as well as ificantly higher AR activity relative to control rats.
Lenses also exhibited a decrease of GSH 2. Labeling for argpyrimidine, a methylglyoxal-derived AGE, and apoptotic molecules revealed that AGEs were highly accumulated in the epithelium Kim et al. Mang, P. Franken, in Encyclopedia of Sleep The Zucker fatty rats have been used for many years in research related to obesity. These animals inherit obesity as an autosomal recessive trait; they are obese, hyperphagic, and hyperinsulinemics but have normal blood glucose levels. These rats have a defect in leptin aling, by a mutation in the leptin receptor.
Species fatties mature looking at the sleep pattern of these animals, NREMS time is increased but more fragmented than in control animals. These suggest that a deficiency in leptin induces abnormalities in sleep—wake pattern, pointing the importance of the energy homeostasis to the normal regulation of sleep architecture. Interestingly, it was found that the expression of prepro-orexin is downregulated in these rats, highlighting a close link between metabolic cues and wake-promoting factors. Moreover, it is important to note that orexins were Species fatties mature studied for their implication in the regulation of feeding, making them a key element linking sleep and metabolism.
These animals have a genetic defect in the leptin receptor, which in obesity and insulin resistance. In response, the endocrine pancreas of ZR undergoes adaptive and compensatory changes. Measurement of the time course of the pathological changes by histological analysis of the pancreatic islet in combination with changes in metabolic parameters is an effective way to reveal disease progression .
In this model, a loss in glucose tolerance occurs first and is accompanied by impaired islet histology, changes in beta-cell mass, and impaired islet function. Thus, early expression of insulin resistance and glucose intolerance in ZR in morphological and functional changes of pancreatic islets, despite their ability to maintain normoglycemia. Studies of the early metabolic defects leading to the development of T2DM in youth have been limited. Kenneth S. Polonsky, Charles F. The hyperinsulinemia precedes hyperglycemia with marked islet hyperplasia and dysmorphogenesis, but by 19 weeks insulin levels drop concomitantly with islet atrophy, in part because of an imbalance of hyperplasia and apoptosis.
In contrast to the male ZDF rat, the female rat has ificant insulin resistance but does not become diabetic unless given a proprietary high-fat diet GMIdeveloped by Genetic Models, Inc. Hansen and C. Burant, unpublished observations.
There is a decrease in peripheral triglyceride and FFA levels in the female rat after institution of the high-fat diet. The underlying genetic defect that in beta-cell failure in the ZDF rat is unknown. The beta-cell and insulin content are not different from those in homozygous normal animals, but insulin promoter activity is doubled in the ZDF rat. A of other gene expression differences have been described in ZDF islets, including decreases in the expression of GLUT2; increases in glucokinase and hexokinase activity ; decreases in mitochondrial metabolism ; accumulation of intraislet lipid and long-chain fatty acyl-CoA, which is associated with abnormal beta-cell secretion , ; and increased accumulation of nitric oxide and ceramide,which is associated with apoptosis.
Other gene expression changes are also found in the prediabetic rat islet. The fixed genetic defect in the male animal le to diabetes, but this defect also interacts with the insulin resistance, because treatment with insulin-sensitizing agents can prevent the onset of diabetes in male and female rats. In the preceding section where the antidiabetic effects of the various species of Opuntia were described, lipid lowering effects were also demonstrated. HDL-C was enhanced by O. Species fatties mature is thus reasonable to assume that at least some components of the lipid profile could be modulated by Opuntia spp.
Cardenas-Medellin et al. These suggest that O. In experiments employing guinea pigs feeding with high cholesterol diet, supplementation with crude pectins of cactus pear 2. The mechanism of HMG-CoA inhibition thereby limiting fat synthesis is the primary target for the statins that does not seem to be shared by the cactus pears pectins. On the other hand, ACAT is membrane-bound protein that synthesizes cholesteryl esters from long-chain fatty acyl-CoA and cholesterol.
Moran-Ramos et al. The key observations for the treatment were:. Increased genes involved in lipid export and production of carnitine palmitoyltransferase-1 and microsomal TG transfer proteins in the liver. Even when glucose lowering effect was not demonstrated for O. With a caution of more research needed in this area, including in mechanistic studies, prickly pear appear to show antiobesity effect in animals. Download as PDF. Set alert. About this. View chapter Purchase book. Cardiovascular Toxicology T.
Boegehold, in Comprehensive Toxicology6. Controversies In Diabetic Neuropathy M. Yorek, in International Review of Neurobiology2.
Franken, in Encyclopedia of SleepZucker rats The Zucker fatty rats have been used for many years in research related to obesity. Type 2 Diabetes Mellitus Kenneth S. The chemical and pharmacological basis of prickly pear cactus Opuntia species as potential therapy for type 2 diabetes and obesity Solomon Habtemariam, in Medicinal Foods as Potential Therapies for Type-2 Diabetes and Associated Diseases ,Species fatties mature
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