Altered dopamine D2 receptor function and binding in obese OLETF rat.

A decrease in D2-like receptor (D2R) binding in the striatum has been reported in obese individuals and drug addicts. Although natural and drug rewards share neural substrates, it is not clear whether such effects also contribute to overeating on palatable meals as an antecedent of dietary obesity. Therefore, we investigated receptor density and the effect of the D2R agonist quinpirole (0.05, 0.5 mg/kg, S.C.) on locomotor activity and sucrose intake in a rat model of diet-induced obesity, the CCK-1 receptor-deficient Otsuka Long Evans Tokushima Fatty (OLETF) rat. Compared to age-matched lean controls (LETO), OLETF rats expressed significantly lower [125I]-iodosulpride binding in the accumbens shell (-16%, p<0.02). Whereas the high dose of quinpirole increased motor activity in both strains equally, the low dose reduced activity more in OLETF. Both doses significantly reduced sucrose intake in OLETF but not LETO rats. These findings demonstrate an altered D2R signaling in obese OLETF rats similar to drug-induced sensitization and suggest a link between this effect and avidity for sucrose in this model.

Unraveling the obesity of OLETF rats.

Cholecystokinin (CCK) is a brain gut peptide that plays an important role in satiety. CCK inhibits food intake by reducing meal size. CCK's satiety actions are mediating through its interaction with CCK1 receptors. Otsuka Long Evans Tokushima Fatty (OLETF) rats are a CCK1 receptor knockout model that allows the study of multiple CCK functions. OLETF rats are hyperphagic with the hyperphagia expressed as a significant increase in the size of meals. OLETF rat obesity is secondary to the hyperphagia and has been proposed to derive from two regulatory deficits. One is secondary to the loss of a feedback satiety signal. The other results from increased dorsomedial hypothalamic NPY expression. Recent studies have examined developmental aspects of altered feeding, body weight and orexigenic signaling in OLETF rats. OLETF rats demonstrate increases in meal size in independent ingestion tests as early as two days of age. OLETF pups are also more efficient in suckling situations. Consistent with such developmental differences, examinations of patterns of hypothalamic gene expression in OLETF pups indicate significant increases in DMH NPY expression as early as postnatal day 15. Access to a running wheel and the resulting exercise have age dependent effects on OLETF food intake and obesity. With running wheel access shortly after weaning, food intake decreases to the levels of LETO controls. When running wheel access is discontinued, food intake temporarily increases resulting in an intermediate phenotype and the absence of diabetes. Together these data demonstrate roles for peripheral CCK and CCK in feeding and body weight control and support the use of the OLETF rat as a model for examining obesity development and for investigating how interventions at critical developmental time points can alter genetic influences on food intake and body weight.

Vascular NADH oxidase is involved in impaired endothelium-dependent vasodilation in OLETF rats, a model of type 2 diabetes.

Superoxide anion can modulate vascular smooth muscle tone and is potentially involved in diabetic vascular complications. The present study was undertaken to characterize both vascular production and the enzymatic source of superoxide anion in type 2 diabetic rats. In the thoracic aorta of OLETF rats, endothelium-dependent relaxation was markedly attenuated compared with that of control (LETO) rats in association with a significant increase in superoxide production (2,421.39 +/- 407.01 nmol x min(-1) x mg(-1)). The increased production of superoxide anion was significantly attenuated by diphenyleneiodonium (DPI; 10 micromol/l), an inhibitor of NAD(P)H oxidase. The production of superoxide anion in response to NADH as a substrate was markedly increased in the vascular homogenates, but NADPH, arachidonic acid, xanthine, and succinate produced only small increases in chemiluminescence. In line with these results, studies using various enzyme inhibitors, such as DPI, allopurinol, rotenone, N(G)-monomethyl-L-arginine, and indomethacin, suggest that the predominant source of superoxide anion in vascular particulate fraction is NADH-dependent membrane-bound oxidase. Furthermore, the expression of p22phox, a major component of vascular NAD(P)H oxidase, was markedly increased in the aorta from OLETF rats compared with that of LETO rats. These findings suggest that upregulated expression of p22phox mRNA and enhanced NADH oxidase activity contribute to the impaired endothelium-dependent vasodilation in OLETF rats.

Troglitazone improves endothelial function and augments renal klotho mRNA expression in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with multiple atherogenic risk factors.

Targeted disruption of the klotho gene induces multiple phenotypes characteristic of human aging, including arteriosclerosis, pulmonary emphysema and osteoporosis. Moreover, we previously observed that insufficient klotho expression in mice leads to endothelial dysfunction. In the present study, we used Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which exhibit hypertension, obesity, severe hyperglycemia and hypertriglyceridemia, and are thus considered an animal model of atherogenic disease, to test the effects of oral administration of troglitazone (200 mg/kg) on renal klotho mRNA expression and endothelial function. Systolic blood pressure, body weight, plasma glucose and triglyceride levels were all significantly higher in 30-week-old OLETF rats than in controls (LETO; Long-Evans Tokushima Otsuka) (p<0.05, n=7). In addition, endothelium-dependent relaxation of the aorta in response to 10(-5) M acetylcholine was significantly attenuated in OLETF rats (p<0.05, n=7), as was renal expression of klotho mRNA. Administration of troglitazone for 10 weeks significantly reduced systolic blood pressure, plasma glucose and triglyceride levels in OLETF rats, while augmenting endothelium-dependent aortic relaxation and renal klotho mRNA expression. These findings suggest that troglitazone protects the vascular endothelium against damage caused by the presence of multiple atherogenic factors.

Functional adaptations in the skeletal muscle microvasculature to endurance and interval sprint training in the type 2 diabetic OLETF rat.

Prevention and treatment of type 2 diabetes includes recommendation to perform aerobic exercise, but evidence indicates that high-intensity exercise training may confer greater benefit. Unique motor recruitment patterns during exercise elicit spatially focused increases in blood flow and subsequent adaptations. Therefore, using 20-wk-old Otsuka Long Evans Tokushima fatty (OLETF) rats with advanced insulin resistance, we examined whether 12 wk of exercise protocols that elicit different motor unit recruitment patterns, endurance exercise (EndEx), and interval sprint training (IST) induce spatially differential effects on endothelial-dependent dilation to acetylcholine (ACh; 1 nM-100 µM) and vasoreactivity to insulin (1-1,000 µIU/ml) in isolated, pressurized skeletal muscle resistance arterioles. Compared with sedentary OLETF rats, EndEx enhanced sensitivity to ACh in second-order arterioles perfusing the "red" (G2A-R) and "white" (G2A-W) portions of the gastrocnemius (EC(50): +36.0 and +31.7%, respectively), whereas IST only increased sensitivity to ACh in the G2A-R (+35.5%). Significant heterogeneity in the vasomotor response to insulin was observed between EndEx and IST as mean endothelin-1 contribution in EndEx was 27.3 ± 7.6 and 25.9 ± 11.0% lower in the G2A-R and G2A-W, respectively. These microvascular effects of exercise were observed in conjunction with training-related improvements in glycemic control (HbA1c: 6.84 ± 0.23, 5.39 ± 0.06, and 5.30 ± 0.14% in sedentary, EndEx, and IST, respectively). In summary, this study provides novel evidence that treatment of advanced insulin resistance in the OLETF rat with exercise paradigms that elicit diverse motor recruitment patterns produce differential adaptive responses in endothelial-dependent dilation and in the complex vascular actions of insulin.

Cilostazol, a phosphodiesterase inhibitor, improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty Rat, a model of spontaneous NIDDM.

AIM: Angiotensin converting enzyme inhibitors and alpha1-adrenergic blockers improve insulin sensitivity, the mechanism of which was considered, at least in part, to be due to the increased blood flow to muscle. The present study aimed to clarify whether cilostazol, a phosphodiesterase inhibitor, improves insulin sensitivity in a model of spontaneous non-insulin dependent diabetes mellitus (NIDDM), Otsuka Long-Evans Tokushima Fatty (OLETF) rat. METHODS: OLETF rats were divided into the two groups at the age of 16 weeks: the cilostazol-supplemented group (cilostazol 40 mg/kg/day) and the normal-diet group. As a non-diabetic control, we used Long-Evans-Tokushima-Otsuka rats (non-diabetic rats). Oral glucose tolerance test and hyperinsulinemic euglycemic clamp was performed at the ages of 23 and 25 weeks, respectively. Serum levels of lipids and leptin were measured. RESULTS: Body weight and abdominal fat was increased in OLETF rats but cilostazol supplementation did not alter them. Insulin sensitivity, as measured by the hyperinsulinemic euglycemic clamp technique, was significantly decreased in OLETF rats (glucose infusion rate: 73.5 +/- 10.0 vs. 41.5 +/- 9.8 micromol/min/kg body weight, p < 0.01). Cilostazol supplementation improved insulin sensitivity partially but significantly 51.0 +/- 5.7 micromol/min/kg body weight, p < 0.05) in OLETF rats at 25 weeks of age, although it did not decrease serum levels of glucose, lipids or leptin. However, this effect was not observed in non-diabetic rats. CONCLUSION: Cilostazol, which is used in diabetic patients for the treatment of obstructive disease of artery, is expected to have a beneficial effect on insulin sensitivity in NIDDM.