Hideki Yamauchi

Long-term exercise down-regulates leptin receptor mRNA in the arcuate nucleus.

The purpose of this study was to investigate the effects of exercise on blood leptin concentrations and expression of leptin receptor subtype-b (Ob-Rb) mRNA in the arcuate nucleus of hypothalamus (ARC). Male Wistar rats (26 weeks old) underwent regular wheel exercise for 12 weeks. The expression of Ob-Rb mRNA in the ARC decreased at the end of the study period despite reductions of abdominal fat-pad weight and serum leptin concentration. Serum 1,5-anhydroglucitol levels were higher in exercising rats, suggesting lower serum insulin levels in exercising rats. Our results suggested that 12-week wheel exercise reduced the expression of Ob-Rb mRNA in the ARC probably through improvement in insulin resistance.

Influence of isoflurane concentration and hypoxia on functional magnetic resonance imaging for the detection of bicuculline-induced neuronal activation.

Our present study shows that transient changes in relative cerebral blood volume (rCBV) induced by stimulation with bicuculline under six different conditions of anesthesia can be detected with high spatial resolution functional magnetic resonance imaging (fMRI). Bicuculline was administered at a low dose to induce neural activation, and no seizure activity was noted. Of the six conditions, the maximal reaction to bicuculline was observed under 1.5% isoflurane in 60% nitrogen and 40% oxygen. Our results imply that the rCBV changes under this level of isoflurane anesthesia with body temperature maintained at 37.5°C are probably suitable for further fMRI studies.

Is the Ipsilateral Cortex Surrounding the Lesion or the Non-Injured Contralateral Cortex Important for Motor Recovery in Rats with Photochemically Induced Cortical Lesions?

Primary Objective:To determine whether the ipsilateral cortex surrounding the lesion or the non-injured contralateral cortex is important for motor recovery after brain damage in the photochemically initiated thrombosis (PIT) model. Research Design:We induced PIT in the sensorimotor cortex in rats and examined the recovery of motor function using the beam-walking test.Methods and Procedures: In 24 rats, the right sensorimotor cortex was lesioned after 2 days of training for the beam-walking test (group 1). After 10 days, PIT was induced in the left sensorimotor cortex. Eight additional rats (group 2) received 2 days training in beam walking, then underwent the beam-walking test to evaluate function. After 10 days of testing, the left sensorimotor cortex was lesioned and recovery was monitored by the beam-walking test for 8 days. Main Outcomes and Results: In group 1 animals, left hindlimb function caused by a right sensorimotor cortex lesion recovered within 10 days after the operation. Right hindlimb function caused by the left-side lesion recovered within 6 days. In group 2, right hindlimb function caused by induction of the left-side lesion after a total of 12 days of beam-walking training and testing recovered within 6 days as with the double PIT model. The training effect may be relevant to reorganization and neuromodulation. Motor recovery patterns did not indicate whether motor recovery was dependent on the ipsilateral cortex surrounding the lesion or the cortex of the contralateral side. Conclusion: The results emphasize the need for selection of appropriate programs tailored to the area of cortical damage in order to enhance motor functional recovery in this model.

The Exercise-Induced Improvement in hyperglycemia is Mediated by DHT Produced in the Skeletal Muscle of Zucker Diabetic Fatty Rats

The ability of exercise to improve hyperglycemia by enhancing glucose metabolism in the skeletal muscle of type 2 diabetic patients is well established. We reported sex steroid hormones can be locally synthesized in skeletal muscle and decrease fasting blood glucose levels in obese rats. Here, we determined whether exercise-induced production of sex steroid hormones in skeletal muscle could directly reverse hyperglycemia in the Zucker diabetic fatty rat model using osmotic mini pump. Thirty Zucker diabetic fatty rats were randomly assigned to the following groups: control, exercise, or exercise with continuous infusion of 5α-reductase inhibitor. The results indicated 6 weeks of exercise significantly reduced serum insulin and fasting glucose levels compared to control group. Dehydroepiandrosterone, 5α-dehydrotestosterone, and 5α-reductase levels were all significantly higher in skeletal muscle of the exercise group. Moreover, exercise increased glucose transporter-4 translocation with a concomitant upregulation of phosphorylated phosphoinositide 3-kinase, protein kinase B and C-ζ/λ. Furthermore, significant correlations were observed between fasting glucose and muscular DHT levels. Interestingly, the observed exercise-induced improvements in serum insulin and fasting glucose levels were all suppressed by administration of 5α-reductase inhibitor. These results indicated the exercise-induced improvements in glucose metabolism signaling and glucose levels may be directly attributed to the increased levels of sex steroid hormones within skeletal muscles.

Facilitated Beam-Walking Recovery during Acute Phase by Kynurenic Acid Treatment in a Rat Model of Photochemically Induced Thrombosis Causing Focal Cerebral Ischemia

We previously demonstrated the presence of activated areas in the non-injured contralateral sensorimotor cortex in addition to the ipsilateral sensorimotor cortex of the area surrounding a brain infarction, using a rat model of focal photochemically induced thrombosis (PIT) and functional magnetic resonance imaging. Using this model, we next applied gene expression profiling to screen key molecules upregulated in the activated area. RNA was extracted from the ipsilateral and contralateral sensorimotor cortex to the focal brain infarction and from the sham controlled cortex, and hybridized to gene-expression profiling arrays containing 1,322 neurology-related genes. Results showed that glycine receptors were upregulated in both the ipsilateral and contralateral cortex to the focal ischemic lesion. To prove the preclinical significance of upregulated glycine receptors, kynurenic acid, an endogenous antagonist to glycine receptors on neuronal cells, was administered intrathecally. As a result, the kynurenic acid significantly improved behavioral recovery within 10 days from paralysis induced by the focal PIT (p < 0.0001), as evaluated with beam walking. These results suggest that intrathecal administration of a glycine receptor antagonist may facilitate behavioral recovery during the acute phase after brain infarction.

Behavioural recovery correlated with MRI in a rat experimental stroke model

Primary objective : To characterize a necrotic lesion using MRI and motor recovery using behavioural methods. Research design : Stroke model based on two steps: (1) development of a lesion using MR-imaging parameters and (2) behavioural recovery. Methods and procedures : Seventy male Sprague-Dawley rats were used. A focal lesion of the right sensorimotor cortex was induced photochemically. Main outcomes and results : The maximum volume of oedema and the lesion damage was reached by ¨ 6 hours. In the lesion area, the apparent diffusion coefficient (ADC) increased from 6 hours, then decreased from 24 hours. All animals spontaneously recovered motor function by day 10, despite the continued presence of the cortical lesion. Conclusions : The results show that this model mimics a core lesion, as well as the late phase in a human stroke episode. This model might be used for longitudinal study of the basic mechanisms of motor recovery.

Histochemical characterization of skeletal muscles in rats with photochemically-induced stroke.

Primary objective: The aim of this study was to assess skeletal muscle showing a complete functional recovery after induction of pan-necrotic lesions in the right sensorimotor cortex in rats. Research design and methods: A focal lesion of the right sensorimotor cortex was induced photochemically. Rats were divided into three groups; the sham-operated group (CON), Stroke (RB) and Stroke plus severed right sciatic nerve (RBD). Main outcomes and results: All RB rats showed complete functional recovery in the beam-walking test within 10 days. The score of CON rats was 7 for 21 days. The wet weight of the soleus muscle (SOL) only in the RB and RBD was significantly greater than in the CON. The cross-sectional area of type I fibres was increased in SOL. Conclusions: It was concluded that the functional recovery was mainly due to increased wet weight and cross-sectional area of type I SOL fibres, which probably reflected the functional reorganization and neuromodulation in the non-damaged contralateral sensorimotor cortex and ipsilateral sensorimotor cortex lateral to the lesion identified in a previous study.

Characterization of fat metabolism in the fatty liver caused by a high-fat, low-carbohydrate diet: A study under equal energy conditions

The pathology of fatty liver due to increased percentage of calories derived from fat without increased overall caloric intake is largely unclear. In this study, we aimed to characterize fat metabolism in rats with fatty liver resulting from consumption of a high-fat, low-carbohydrate (HFLC) diet without increased caloric intake. Four-week-old male Sprague-Dawley rats were randomly assigned to the control (Con) and HFLC groups, and rats were fed the corresponding diets ad libitum. Significant decreases in food intake per gram body weight were observed in the HFLC group compared with that in the Con group. Thus, there were no significant differences in body weights or caloric intake per gram body weight between the two groups. Marked progressive fat accumulation was observed in the livers of rats in the HFLC group, accompanied by suppression of de novo lipogenesis (DNL)-related proteins in the liver and increased leptin concentrations in the blood. In addition, electron microscopic observations revealed that many lipid droplets had accumulated within the hepatocytes, and mitochondrial numbers were reduced in the hepatocytes of rats in the HFLC group. Our findings confirmed that consumption of the HFLC diet induced fatty liver, even without increased caloric intake. Furthermore, DNL was not likely to be a crucial factor inducing fatty liver with standard energy intake. Instead, ultrastructural abnormalities found in mitochondria, which may cause a decline in β-oxidation, could contribute to the development of fatty liver.