Decreased responsiveness to dietary fat in Otsuka Long-Evans Tokushima fatty rats lacking CCK-A receptors.
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Adult Otsuka Long-Evans Tokushima fatty (OLETF) rats lack functional cholecystokinin A (CCK-A) receptors, are diabetic, hyperphagic, and obese, and have patterns of ingestion consistent with a satiety deficit secondary to CCK insensitivity. Because dietary fat potently stimulates CCK release, we examined how dietary fat modulates feeding in adult male OLETF rats and their lean [Long-Evans Tokushima (LETO)] controls. High-fat feeding produced sustained overconsumption of high-fat diet (30% corn oil in powdered chow) over a 3-wk period in OLETF but not LETO rats. We then assessed the ability of gastric gavage (5 ml, 1-2 kcal/ml x 15 s) or duodenal preloads (1 kcal/ml, 0.44 ml/min x 10 min) of liquid carbohydrate (glucose), protein (peptone), or fat (Intralipid) to suppress subsequent 30-min 12.5% glucose intake in both strains. In OLETF rats, gastric and duodenal fat preloads were significantly less effective in suppressing subsequent intake than were equicaloric peptone or glucose. These results demonstrate that OLETF rats fail to compensate for fat calories and suggest that their hyperphagia and obesity may stem from a reduced ability to process nutrient-elicited gastrointestinal satiety signals. (+info)
Examination of the pathogenesis of diabetic nephropathy in OLETF rats.
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We conducted protein loading to examine the progression and pathogenesis of diabetic nephropathy. For this experiment, male OLETF, LETO, F344 and BN rats were used. This experiment was performed on rats between 5 and 30 weeks of age. Examination parameters included body weight, food intake, oral glucose tolerance test (OGTT), urinary protein level (UP), urinary albumin level (UA), glomerular filtration rate (GFR), kidney weights, light microscopy (LM) and electron microscopy (EM). In the protein-loaded OLETF group, the UP level was markedly increased 20 weeks or more after birth. In OLETF control group, GFR were higher than those in other strains. Glomerular hypertrophy and kidney weights were markedly increased in protein-loaded groups in OLETF rats. Thirty weeks after birth, EM showed that the number of polyethyleneimine (PEI) of the glomerular basement membrane (GBM) in protein-loaded OLETF group was significantly decreased compared to that in control group. These changes in OLETF rats were more marked in the protein-loaded group than those in the control group. LM showed that the number of exudative lesions with fibrin-cap in the protein-loaded OLETF group was significantly increased than those in control group. In OLETF rats, protein loading caused deterioration of nephropathy at 30 weeks of age. Therefore, it was demonstrated that not only blood sugar control but also protein intake factors play important roles in the deterioration of nephropathy in OLETF rats. (+info)
Taurine improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous type 2 diabetes.
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BACKGROUND: Taurine, a potent antioxidant, has been reported to improve streptozotocin-induced diabetes mellitus, in which the development of diabetes results from an attack by oxygen free radicals on pancreatic beta cells. However, taurine also increases the excretion of cholesterol via conversion to bile acid and would be expected to improve insulin resistance. OBJECTIVE: The effects of taurine on insulin sensitivity were examined in a model rat of insulin resistance and type 2 diabetes-the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. DESIGN: Male OLETF rats were divided into 2 groups at the age of 16 wk: a taurine-supplemented group and an unsupplemented group. As a nondiabetic control, Long-Evans-Tokushima-Otsuka rats were used. An oral-glucose-tolerance test and hyperinsulinemic euglycemic clamp were performed at the ages of 23 and 25 wk. RESULTS: The OLETF rats had hyperglycemia and insulin resistance and they had a greater accumulation of abdominal fat than did control rats. Abdominal fat accumulation, hyperglycemia, and insulin resistance were significantly lower in the taurine-supplemented group than in the unsupplemented group. Serum and liver concentrations of triacylglycerol and cholesterol were significantly higher in the OLETF rats than in the control rats and were significantly lower in the taurine-supplemented group than in the unsupplemented group, presumably because of the increased secretion of cholesterol into bile acid. Taurine-supplemented rats also showed higher nitric oxide secretion, evidenced by increased urinary excretion of nitrite. CONCLUSION: Taurine effectively improves metabolism in OLETF rats by decreasing serum cholesterol and triacylglycerol, presumably via increased secretion of cholesterol into bile acid and decreased production of cholesterol because of increased nitric oxide production. (+info)
Identification of genes specifically expressed in the accumulated visceral adipose tissue of OLETF rats.
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The Otsuka Long-Evans Tokushima fatty (OLETF) rat is an animal model of type 2 diabetes, characterized by abdominal obesity, insulin resistance, hypertension, and dyslipidemia. To elucidate the underlying molecular mechanism of obesity and its related complications, we used representational difference analysis and identified the genes more abundantly and specifically expressed in the visceral adipose tissue (VAT) of obese OLETF rats compared with the diabetes-resistant counterpart, that is, Long-Evans Tokushima Otsuka (LETO) rats. By Northern blot analysis, we confirmed the differential expression of 13 genes, including 3 novel genes. The upregulated expression of well-characterized lipid metabolic enzymes, such as lipoprotein lipase, phosphoenolpyruvate carboxykinase, and cholesterol esterase, were observed in VAT of OLETF rats. We demonstrated the differential expression of secreted proteins in VAT of OLETF rats, such as thrombospondin 1 and contrapsin-like protease inhibitor. In contrast to lipid enzymes, the secreted proteins revealed exclusive mRNA expression and they were not detected in VAT of LETO rats. Furthermore, the novel genes OL-16 and OL-64 were also expressed specifically in VAT of OLETF rats and were absent in that of LETO rats and other tissues, including subdermal and brown adipose tissues. The C-terminal partial amino acid sequence of OL-64 revealed that it showed approximately 40% homology with alpha(1)-antitrypsin and it seemed to be a new member of the serine proteinase inhibitor (SERPIN) gene family. VAT of OLEFT rats had a unique gene expression profile, and the accumulated VAT-specific known and novel secreted proteins may play a role(s) in the pathogenesis of obesity and its related complications. (+info)
The diurnal rhythm of energy expenditure differs between obese and glucose-intolerant rats and streptozotocin-induced diabetic rats.
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Otsuka Long Evans Tokushima Fatty (OLETF) rats were developed as a model of noninsulin-dependent diabetes mellitus (NIDDM) with mild obesity. Changes in carcass composition and in the daily profile of energy expenditure were examined before and after manifestation of diabetes (8 and 24 wk, respectively), and compared with the normal control Long Evans Tokushima (LETO) rats and streptozotocin (STZ)-induced diabetic LETO rats. OLETF rats had greater body weights than LETO rats and significantly greater absolute and relative fat weights. A diurnal rhythm of energy expenditure associated with two peaks was observed in LETO rats, but the two peaks were not apparent in OLETF rats at 24 wk of age. A diurnal rhythm associated with one peak was observed in STZ-induced diabetic LETO rats. Energy derived from fat constituted this peak; the pattern of the daily energy expenditure was significantly different from that of either nontreated LETO or OLETF rats at 24 wk of age. NIDDM in OLETF rats at 24 wk of age has only a small role in modification of the diurnal rhythm of energy expenditure, whereas STZ-induced diabetes significantly affected the rhythm. (+info)
Coronary capillary remodeling in non-insulin-dependent diabetic rats: amelioration by inhibition of angiotensin converting enzyme and its potential clinical implications.
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Using Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of human non-insulin-dependent diabetes mellitus (NIDDM) that exhibits hypertension, obesity, hyperglycemia and hyperlipidemia, the role of local angiotensin II in cardiovascular complications at early stages of NIDDM was characterized. OLETF rats were given an angiotensin converting enzyme (ACE) inhibitor, cilazapril (10 mg/kg/day) or vehicle from the age of 5 weeks to 20 weeks. Arteriolar, intermediate and venular capillary proportions were determined by the double-staining method and levels of collagen and non-collagenous proteins were determined by the selective dye-binding method in heart tissues. In OLETF rats at 20 weeks of age, capillary network remodeling (i.e., an increase in arteriolar portions and a decrease in venular portions) and an increase in collagen content were detected. Cilazapril not only exerted favorable effects on markers of diabetes, but also prevented capillary network remodeling and ameliorated the increase in collagen content. These results suggest that 1) capillary network remodeling and increase in extracellular matrix protein levels precede the onset of overt NIDDM in OLETF rats, and 2) angiotensin II may be involved in the pathogenesis of cardiac complications in the early stages of NIDDM. (+info)
Startle and sensorimotor gating in rats lacking CCK-A receptors.
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Otsuka Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a genetic mutation. Previous studies have shown that CCK-A receptors seem to play a role in the regulation of prepulse inhibition (PPI) of the startle reflex, an operational measure of sensorimotor gating. This study investigated baseline and drug-disrupted PPI in OLETF rats and their non-mutant counterparts, Long Evans Tokushima Otsuka (LETO) rats. Baseline PPI did not differ significantly between the two rat genotypes but OLETF rats exhibited a higher acoustic startle response compared to LETO rats. Amphetamine (2 mg/kg), and the non-competitive NMDA antagonist, dizocilpine (0.1 mg/kg), disrupted PPI in LETO rats but not in the OLETF rats. Apomorphine (0.5 mg/kg) failed to disrupt PPI in both LETO and OLETF rats, and haloperidol (0.5 mg/kg) produced a comparable facilitation of PPI in both groups. In a separate study, OLETF rats were found to be less sensitive to the locomotor stimulating effects of amphetamine. These results suggest that CCK-A receptors play a significant role in the behavioral effects of amphetamine and dizocilpine. The PPI response of OLETF rats to amphetamine and dizocilpine is similar to normal rats pretreated with atypical antipsychotics, suggesting that CCK-A receptors may play an important role in the restoration of drug-disrupted PPI by antipsychotics. (+info)
Identification of epistatic interactions involved in non-insulin-dependent diabetes mellitus in the Otsuka Long-Evans Tokushima Fatty rat.
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The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type non-insulin-dependent diabetes mellitus (NIDDM) in humans. Our present investigation was designed to identify epistatic interactions influencing NIDDM by performing least squares analysis of variance of all pairs of informative markers in 160 F2 progenies bred from an intercross of OLETF and Fischer-344 rats. We identified four interactions between Nidd15/of (chromosome 7) and Nidd16/of (chromosome 14), Nidd15/of and Nidd17/of (chromosome 15), Nidd16/of and Nidd18/of (chromosome 15), and Nidd16/of and Nidd19/of (chromosome 17), which account for a total of approximately 40% of the genetic variation of entire glucose levels after glucose challenge in the F2. The Nidd16/of locus, which is involved in three of four digenic interactions, and the Nidd19/of are likely to correspond to Nidd2/of and Nidd14/of, NIDDM loci previously identified in the F2 by single-QTL model and multiple-QTL model, respectively, while Nidd15/of, Nidd17/of and Nidd18/of loci reflect novel NIDDM loci. An aberrant increase of the entire glucose level due to synergism occurs in the double OLETF homozygote genotype of Nidd15/of and Nidd16/of, and of Nidd16/of and Nidd19/of, as well as in the OLETF homozygote genotypes of Nidd15/of and Nidd16/of, respectively, combined with the heterozygote genotypes of Nidd17/of and Nidd18/of. These findings demonstrate that inter-allelic interactions are likely to be an important component of NIDDM susceptibility. (+info)