Biomedical subjects

Takuya Chiba

Publications and source records attributed to Takuya Chiba.

13 recordsLinked to original sources

PubMed2006

Calorie restriction initiated at middle age improved glucose tolerance without affecting age-related impairments of insulin signaling in rat skeletal muscle.

Calorie restriction (CR) may affect glucose tolerance via modulation of the insulin action in skeletal muscle. The present study investigated the effect of CR initiated at middle age in rats bearing glucose intolerance, in comparison with CR at a younger age. Male F344 rats at 2.5 and 18months (mo) of age were fed ad libitum (AL) or 30% CR diets for 4-4.5mo, subjected to glucose tolerance testing, and then sacrificed 15min after intraperitoneal glucose or saline injection to evaluate glucose-stimulated insulin response and subsequent activation of insulin signaling molecules. The protein abundance of phosphorylated (p) insulin receptors, p-Akt, and p-atypical PKC and the membrane fraction of glucose transporter 4 in quadriceps femoris muscle (QFM) were analyzed by EIA or immunoblotting. CR initiated either at young or middle age improved glucose tolerance with a lower serum insulin response to glucose. However, middle-aged CR did not improve aging-related impairments in insulin signaling in QFM. The present results emphasized the possibilities of CR activation of an insulin-independent mechanism in skeletal muscle and also of the involvement of non-muscle tissues in glucose uptake.

Adipose Tissue↗

PubMed2006

Hepatic gene expression profile of lipid metabolism in rats: Impact of caloric restriction and growth hormone/insulin-like growth factor-1 suppression.

We investigated the role of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis on caloric restriction (CR) using male wild-type and transgenic homozygous dwarf rats bearing an antisense GH transgene and their F1 heterozygous progeny fed either ad libitum or subjected to 30% CR. CR predominantly altered expression of hepatic genes involved in the stress response, xenobiotic metabolism, and lipid metabolism. Most gene expressions involved in stress response and xenobiotic metabolism were regulated in a GH/IGF-1-dependent manner, and those involved in lipid metabolism were regulated in a GH/IGF-1-independent manner. Moreover, CR enhanced the gene expression involved in fatty acid synthesis after feeding and those encoding mitochondrial beta-oxidation enzymes during food shortage, probably via transcriptional regulation by peroxisome proliferator-activated receptor alpha. These results, taken together with serum biochemical measures and hepatic triglyceride content, suggest that CR promotes lipid utilization through hepatic transcriptional alteration and prevents hepatic steatosis in a GH/IGF-1-independent manner.

Animals↗

PubMed2006

Effect of leptin on hypothalamic gene expression in calorie-restricted rats.

Diminished leptin signaling to the arcuate nucleus of hypothalamus (ARH) may induce calorie restriction (CR)-specific neuroendocrine and metabolic adaptation, which is potentially relevant to the effect of CR. The present study investigated whether restoration of leptin signaling to the ARH could reverse CR-induced alterations in neuropeptide gene expression in rats. Male F344 rats, fed ad libitum or a 30% CR diet from 6 weeks of age, received leptin or vehicle intracerebroventricularly for 14 days via osmotic mini-pumps implanted in the subcutis at 34 weeks of age. The messenger RNA levels were quantified by real-time reverse transcription-polymerase chain reaction using total RNA extracted from microdissected tissues containing the ARH. The results indicated that leptin administration reversed the upregulated expression of neuropeptide Y and agouti-related protein genes in CR rats, suggesting the possibility of a role for the leptin-ARH pathway in the effect of CR.

Agouti Signaling Protein↗

PubMed2005

Acute stress response in calorie-restricted rats to lipopolysaccharide-induced inflammation.

Calorie restriction (CR) reduces morbidity and mortality in a wide range of organisms, possibly through the stress response machinery. We analyzed the acute phase response of CR rats to lipopolysaccharide (LPS)-induced inflammatory challenge. Six-month-old male F344 rats, fed ad libitum (AL) or a 30% calorie-restricted diet from 6 weeks of age, received an intravenous LPS injection and were then sacrificed between 0 and 8 h. CR attenuated liver injury without reduction in the plasma concentrations of proinflammatory cytokines or nitric oxide (NO). Western blotting analysis of liver tissue demonstrated that CR did not affect the degradation of cytoplasmic I-kappaB and subsequent nuclear translocation of NF-kappaB, a key transcription factor after inflammatory challenge. We also analyzed the liver gene expression profiles at 0, 1 and 4 h with DNA arrays and cluster analysis. Compared with the AL group, CR upregulated the expression of several genes for inflammatory mediators or their related molecules at 0 h, but not at 1 or 4 h. CR downregulated genes for energy or xenobiotic metabolism and stress response proteins at 0 h. At 1 h, the relatively downregulated genes by CR were those for proteases and the ubiquitin-proteasome pathway. The present results suggest that CR attenuates liver injury without suppression of the proinflammatory response, and that the protective effect emerges from constitutively, rather than inductively, expressed gene products.

Acute Disease↗

PubMed2004

SV40 T antigen interacts with Nbs1 to disrupt DNA replication control.

Nijmegen breakage syndrome (NBS) is characterized by radiation hypersensitivity, chromosomal instability, and predisposition to cancer. Nbs1, the NBS protein, forms a tight complex with Mre11 and Rad50, and these interactions contribute to proper double-strand break repair. The simian virus 40 (SV40) oncoprotein, large T antigen (T), also interacts with Nbs1, and T-containing cells experience chromosomal hyperreplication in a manner dependent on T/Nbs1 complex formation. A substantial fraction of NBS-deficient fibroblasts reinitiate DNA replication in discrete regions, and wild-type Nbs1 corrects this defect. Similarly, synthesis of an N-terminal Nbs1 fragment induced DNA rereplication and tetraploidy, in NBS-deficient but not NBS-proficient cells. Moreover, SV40 origin-containing DNA hyperreplicated in T-containing NBS-deficient cells by comparison with T-containing, Nbs1-reconstituted derivatives. Thus, Nbs1 suppresses rereplication of cellular DNA and SV40 origin-containing replicons, and T targets Nbs1, thereby enhancing the yield of new SV40 genomes during viral DNA replication.

Acid Anhydride Hydrolases↗

PubMed2004

Expression of DNase gamma during Fas-independent apoptotic DNA fragmentation in rodent hepatocytes.

Endonuclease-induced DNA fragmentation is a hallmark of apoptosis. DNase gamma (DNase gamma) was recently identified as one of the endonucleases responsible for apoptotic DNA fragmentation. In this study, immunohistochemistry for DNase gamma was performed on paraffin sections of rodent liver in well-defined models of hepatocyte apoptosis induced by Fas antibody (Fas) or cycloheximide (CHX), and necrosis induced by lipopolysaccharide (LPS) or carbon tetrachloride (CCl4). DNase gamma immunoreactivity was compared with TdT-mediated dUTP nick-end labeling (TUNEL) reactivity. Our results showed TUNEL reactivity in both apoptotic and necrotic hepatocytes. DNase gamma immunoreactivity was not detected during LPS-induced or CCl4-induced hepatocyte necrosis. In contrast, it was evident during CHX-induced, but not Fas-induced, apoptotic DNA fragmentation. These findings suggest that DNase gamma plays an important role in Fas-independent apoptotic DNA fragmentation in hepatocytes.

Animals↗

PubMed2004

Mouse testis transcriptome revealed using serial analysis of gene expression.

We applied serial analysis of gene expression (SAGE) to the mouse testis to reveal the global gene expression profile and to identify senescence-dependent changes in that profile. A total of 61,929 SAGE tags, including 19,323 unique tags, were obtained from 3- and 29-month-old BDF1 mice and 14-month-old SAMP1 mice. Genes highly expressed in the testis included those associated with spermatogenesis, protein metabolism, energy metabolism, growth and differentiation, and signal transduction. Testes from old mice of both strains appeared atrophied. Morphological examination of aged testes revealed extremely thin seminiferous epithelia and significantly decreased numbers of spermatids and spermatocytes. Despite the physical deterioration, no gross changes in the gene expression profile were apparent in the testes of old BDF1 mice. However, in 14-month-old SAMP1 mice, protamine 2 gene transcription was approximately 50% lower than in BDF1 mice. This reduction may be associated with the oligozoospermia and early decline in reproductive performance of SAMP1 mice. Our SAGE results are the first quantitative gene expression profile of the mouse testis and provide a reliable transcriptome reference for this organ.

Age Factors↗

PubMed2004

A transgenic dwarf rat model as a tool for the study of calorie restriction and aging.

We have previously reported a long-lived transgenic dwarf rat model, in which the growth hormone (GH)-insulin like growth factor (IGF)-1 axis was selectively suppressed by overexpression of antisense GH transgene. Rats heterozygous for the transgene (tg/-) manifest phenotypes similar to those in calorie-restricted (CR) rats. To further characterize the transgenic rat in comparison with CR rats, the present study evaluated glucose and insulin tolerance in tg/- and control Wistar (-/-) rats at 6-9 months of age. Rats were fed ad libitum (AL) or 30% CR from 6 weeks of age. In CR rats, glucose disposal after glucose load was facilitated without any significant surge of serum insulin, and insulin tolerance test also indicated increased insulin sensitivity. In transgenic rats, similar findings were observed after glucose and insulin load, and CR in tg/- rats further facilitated glucose disposal during glucose and insulin tolerance tests. These findings suggest the presence of both common and separate mechanisms regulating the glucose-insulin system between CR and the reduced GH-IGF-1 axis paradigms. The transgenic rat model is, therefore, a useful one for studies of CR and aging.

Aging↗

PubMed2003

Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction.

A reduced growth hormone (GH)-insulin-like growth factor (IGF)-1 axis is associated with an extension of lifespan in laboratory rodents. Several phenotypes of such animal models resemble those induced by caloric restriction (CR). Using a transgenic male Wistar rat model whose GH-IGF-1 axis was moderately suppressed by overexpression of the antisense GH transgene (tg), we elucidated a relationship between the effects of a reduced GH-IGF-1 axis and CR for some biomarkers of aging, lifespan, and pathologies. Heterozygous (tg/-) rats fed ad libitum (AL) had a dwarf phenotype similar to that of control nontransgenic (-/-) rats subjected to 30% CR from 6 wk of age. Both the reduced GH-IGF-1 axis and CR extended lifespan to a similar extent, although the effect of CR seemed to be greater. There was an additive effect of CR to lifespan extension when tg/- rats were subjected to CR. Pathologic analyses indicated that the preventive effect of CR on selected diseases was greater than that of the reduced GH-IGF-1 axis. The present study suggests that CR affects aging and longevity by mechanisms other than suppression of the GH-IGF-1 axis, although CR might exhibit its effects partly through the reduced GH-IGF-1 axis.

Adenoma↗

PubMed2002

Anti-aging effects of caloric restriction: Involvement of neuroendocrine adaptation by peripheral signaling.

Many hormonal signals from peripheral tissues contribute to the regulation of energy homeostasis and food intake. These regulators including leptin, insulin, and ghrelin, modulate the orexigenic and anorexigenic neuropeptide expression in hypothalamic nuclei. The anti-aging effects of caloric restriction have been explained from an evolutional viewpoint of the adaptive response of the neuroendocrine and metabolic response systems to maximize survival during periods of food shortage. In organisms, excess energy is stored in adipose tissues as a triglyceride preparation for such survival situations. Adipose tissue has recently been recognized as an endocrine organ, and leptin, as secreted by adipocyte, seems to be an especially important factor for the adaptive response to fasting and neuroendocrine alterations under caloric restriction. In this review, we discuss the potential involvement of neuroendocrine modulators in longevity and the anti-aging effects of caloric restriction.

Adaptation, Physiological↗

PubMed2002

Lifespan extension by caloric restriction: an aspect of energy metabolism.

Caloric restriction (CR) may retard aging processes and extend lifespan in organisms by altering energy-metabolic pathways. In CR rodents, glucose influx into tissues is not reduced, as compared with control animals fed ad libitum (AL), although plasma concentrations of glucose and insulin are lower. Gene expression profiles in rodents have suggested that CR promotes gluconeogenesis and fatty acid biosynthesis in skeletal muscle. In the liver, CR promotes gluconeogenesis but decreases fatty acid synthesis and glycolysis. In lower organisms such as yeasts and nematodes, incomplete blocks in steps of insulin/insulin-like growth factor-1 (IGF-1) signal pathway extend lifespan. The life-prolonging effect of CR in yeasts requires NPT1 and SIR2 genes, both of which relate to sensing energy status and silencing genes. These findings stress the substantial role of energy metabolism on CR. Future studies on metabolic adaptation and gene silencing with regard to lower caloric intake will be warranted to understand the mechanisms of the anti-aging and life-prolonging effects of CR.

Aging↗

PubMed2002

Life span extension by reduction in growth hormone-insulin-like growth factor-1 axis in a transgenic rat model.

The longer life span in dwarf mice suggests that a reduction in the growth hormone (GH)-insulin-like growth factor (IGF)-1 axis retards aging and extends the life span in mammals. We tested this hypothesis in a transgenic strain of rats whose GH gene was suppressed by an anti-sense GH transgene. Male rats homozygous for the transgene (tg/tg) had a reduced number of pituitary GH cells, a lower plasma concentration of IGF-1, and a dwarf phenotype. Heterozygous rats (tg/-) had an intermediate phenotype in plasma IGF-1, food intake, and body weight between tg/tg and control (-/-) rats. The life span of tg/tg rats was 5 to 10% shorter than -/- rats. In contrast, the life span of tg/- rats was 7 to 10% longer than -/- rats. Pathological analysis suggested that neoplasms caused earlier death in tg/tg rats; in contrast, tg/- rats had reduced nonneoplastic diseases and a prolonged life span. Immunological analysis revealed a smaller population and lower activity of splenic natural killer cells in tg/tg rats. The results of the present study support the hypothesis, but suggest that there is an optimal level of the GH-IGF-1 axis to maximize survival in mammals.

Animals↗

PubMedDate not supplied

Effects of caloric restriction on gene expression in the arcuate nucleus.

Neuroendocrine alterations that repress energy-costly physiologic processes such as reproduction and growth and induce stress responses, might underlie the antiaging effect of caloric restriction (CR). Neurons in the arcuate nucleus of the hypothalamus (ARH) might have a pivotal role in these neuroendocrine alterations. We investigated the effects of CR on gene expression of neuropeptide Y (NPY), proopiomelanocortin (POMC), growth hormone-releasing hormone (GHRH), somatostatin (SRIH), and cyclophilin (CP) in the ARH in male F344 rats at 6 months of age. Rats were fed ad libitum or a 30% caloric restricted diet with a modified alternate-days feeding regimen from 6 weeks of age. Reverse transcription-polymerase chain reaction (RT-PCR) methods were used to quantify mRNA levels over multiple time points during the 12-h/12-h dark/light cycle over a 2-days feeding cycle. The present study demonstrated that CR increased NPY-mRNA levels, but decreased POMC, GHRH, and CP mRNA levels differentially over the feeding cycle. The SRIH level was not significantly affected by CR. The present results support the neuroendocrine hypothesis of CR.

Analysis of Variance↗