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5. Mechanisms underlying retardation of aging by dietary energy restriction.

Author

Shimokawa, Isao

Subjects
*NEUROPEPTIDE Y, *FORKHEAD transcription factors, *AGING, *TRANSCRIPTION factors, *GENE knockout, *CARDIAC amyloidosis
Abstract

Moderate restriction of dietary energy intake, referred to here as dietary restriction (DR), delays aging and extends lifespan in experimental animals compared with a diet of ad libitum feeding (AL) control animals. Basic knowledge of the mechanisms underlying the effects of DR could be applicable to extending the healthspan in humans. This review highlights the importance of forkhead box O (FoxO) transcription factors downstream of the growth hormone‐insulin‐like growth factor 1 signaling in the effects of DR. Our lifespan studies in mice with heterozygous Foxo1 or Foxo3 gene knockout indicated differential roles of FoxO1 and FoxO3 in the tumor‐inhibiting and life‐extending effects of DR. Subsequent studies suggested a critical role of FoxO3 in metabolic and mitochondrial bioenergetic adaptation to DR. Our studies also verified hypothalamic neuropeptide Y (Npy) as a vital neuropeptide showing pleiotropic and sexually dimorphic effects for extending the healthspan in the context of nutritional availability. Npy was necessary for DR to exert its effects in male and female mice; meanwhile, under AL conditions, the loss of Npy prevented obesity and insulin resistance only in female mice. Overnutrition disrupts FoxO‐ and Npy‐associated metabolic and mitochondrial bioenergetic adaptive processes, causing the acceleration of aging and related diseases. [ABSTRACT FROM AUTHOR]

Published
2023
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9. Calorie restriction initiated at a young age activates the Akt/PKCζ/λ-Glut4 pathway in rat white adipose tissue in an insulin-independent manner

Author

Park, Seongjoon, Komatsu, Toshimitsu, Hayashi, Hiroko, Yamaza, Haruyoshi, Chiba, Takuya, Higami, Yoshikazu, Kuramoto, Kazunao, and Shimokawa, Isao

Abstract

Abstract: Calorie restriction (CR) may exert an anti-aging effect through a metabolic adaptation to limited energy intake. The present study investigated the effect of CR on insulin signaling in response to glucose load in the epididymal adipose tissue of male F344 rats at 7 and 22 months of age. Young and middle-aged rats were fed ad libitum (AL) or 30% CR diets for 4 months, underwent glucose tolerance tests and were sacrificed 15 min after an intraperitoneal glucose or saline injection to evaluate glucose-stimulated insulin response and subsequent activation of insulin signaling molecules in the adipose tissue. In the 7- and 22- month AL groups, glucose administration increased serum insulin levels and also increased phosphorylated (p) levels of the insulin receptor (IR), v-akt murine thymoma viral oncogene homolog (Akt), protein kinase C (PKC) ζ/λ and the membrane fraction of glucose transporter 4 (mGlut4). In contrast, in the 7-month CR group, p-Akt, p-PKCζ/λ and mGlut4 levels were upregulated without glucose stimulation; the glucose load augmented the p-IR level but there was no additional activation of the downstream molecules. In the 22-month CR group, these unexpected findings were not observed. In summary, basal levels of insulin signaling molecules such as p-Akt, p-PKCζ/λ, and mGlut4 were significantly increased with a low insulin response in the 7-month CR group. The present results suggest the presence of an age-specific insulin-independent mechanism that is induced by CR to regulate energy metabolism in white adipose tissue.

Published
2024
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12. Targeting miR‐223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds

Author

de Kerckhove, Maiko, Tanaka, Katsuya, Umehara, Takahiro, Okamoto, Momoko, Kanematsu, Sotaro, Hayashi, Hiroko, Yano, Hiroki, Nishiura, Soushi, Tooyama, Shiho, Matsubayashi, Yutaka, Komatsu, Toshimitsu, Park, Seongjoon, Okada, Yuka, Takahashi, Rina, Kawano, Yayoi, Hanawa, Takehisa, Iwasaki, Keisuke, Nozaki, Tadashige, Torigoe, Hidetaka, Ikematsu, Kazuya, Suzuki, Yutaka, Tanaka, Katsumi, Martin, Paul, Shimokawa, Isao, and Mori, Ryoichi

Published
2018
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16. Anticancer agent α-sulfoquinovosyl-acylpropanediol enhances the radiosensitivity of human malignant mesothelioma in nude mouse models

Author

Inamasu, Eiko, primary, Tsuchiya, Tomoshi, additional, Yamauchi, Motohiro, additional, Nishi, Kodai, additional, Matsuda, Katsuya, additional, Sugawara, Fumio, additional, Sakaguchi, Kengo, additional, Mori, Ryoichi, additional, Matsumoto, Keitaro, additional, Miyazaki, Takuro, additional, Hatachi, Go, additional, Doi, Ryoichiro, additional, Watanabe, Hironosuke, additional, Tomoshige, Koichi, additional, Matsuda, Naoki, additional, Higami, Yoshikazu, additional, Shimokawa, Isao, additional, Nakashima, Masahiro, additional, and Nagayasu, Takeshi, additional

Published
2021
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25. The Role of Neuropeptide Y in Adipocyte-Macrophage Crosstalk during High Fat Diet-Induced Adipose Inflammation and Liver Steatosis

Author

Park, Seongjoon, Komatsu, Toshimitsu, Hayashi, Hiroko, Mori, Ryoichi, Shimokawa, Isao, Park, Seongjoon, Komatsu, Toshimitsu, Hayashi, Hiroko, Mori, Ryoichi, and Shimokawa, Isao

Abstract

Obesity is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD), which is initiated by adipocyte-macrophage crosstalk. Among the possible molecules regulating this crosstalk, we focused on neuropeptide Y (NPY), which is known to be involved in hypothalamic appetite and adipose tissue inflammation and metabolism. In this study, the NPY−/− mice showed a marked decrease in body weight and adiposity, and lower free fatty acid and adipose inflammation without food intake alteration during a high fat diet (HFD). Moreover, NPY deficiency increased the thermogenic genes expression in brown adipose tissue. Notably, NPY-mRNA expression was upregulated in macrophages from the HFD mice compared to that from the mice on a standard diet. The NPY-mRNA expression also positively correlated with the liver mass/body weight ratio. NPY deletion alleviated HFD-induced adipose inflammation and liver steatosis. Hence, our findings point toward a novel intracellular mechanism of NPY in the regulation of adipocyte-macrophage crosstalk and highlight NPY antagonism as a promising target for therapeutic approaches against obesity and NAFLD., Biomedicines, 9(11), art. no. 1739; 2021

Published
2021

36. Involvement of insulin-like growth factor-1 in the effect of caloric restriction: regulation of plasma adiponectin and leptin

Author

Yamaza, Haruyoshi, Komatsu, Toshimitsu, To, Kazuo, Toyama, Hiroaki, Chiba, Takuya, Higami, Yoshikazu, and Shimokawa, Isao

Subjects
Growth factors -- Properties, Growth factors -- Influence, Longevity -- Research, Lectins -- Properties, Lectins -- Control, Bioenergetics -- Control, Bioenergetics -- Influence, Energy metabolism -- Control, Energy metabolism -- Influence, Blood plasma -- Properties, Adipose tissues -- Properties, Health, Seniors
Abstract

Insulin-like growth factor (IGF)-1 signaling might partly mediate effects of caloric restriction (CR), an experimental intervention for increasing longevity in mammals. The present study evaluated effects of recombinant human (rh)IGF-1 infusion on adipokine levels in CR and transgenic (Tg) dwarf rats with the reduced growth hormone--IGF-1 axis, which shared similar body weight and food intake. At 9 months of age, each rat received a continuous infusion of rhIGF-1 for 14 days, and rats received an injection of glucose after overnight fasting. Infusion of rhlGF-1 had metabolic effects in all rat groups although it did not affect insulin sensitivity in any of the groups. In addition, plasma adiponectin was decreased to the control group levels and plasma leptin was further reduced in CR and Tg rats. The similarity of phenotypes and adipokine responses to rhlGF-1 between CR and Tg rats supports a role for reduced IGF-1 signaling in the CR effect.

Published
2007

37. Overexpression of the adiponectin gene mimics the metabolic and stress resistance effects of calorie restriction, but not the anti-tumor effect

Author

Kamohara, Ryotaro, Yamaza, Haruyoshi, Tsuchiya, Tomoshi, Komatsu, Toshimitsu, Park, Seongjoon, Hayashi, Hiroko, Chiba, Takuya, Mori, Ryoichi, Otabe, Shuichi, Yamada, Kentaro, Nagayasu, Takeshi, Shimokawa, Isao, Kamohara, Ryotaro, Yamaza, Haruyoshi, Tsuchiya, Tomoshi, Komatsu, Toshimitsu, Park, Seongjoon, Hayashi, Hiroko, Chiba, Takuya, Mori, Ryoichi, Otabe, Shuichi, Yamada, Kentaro, Nagayasu, Takeshi, and Shimokawa, Isao

Abstract

Adiponectin (Adipoq), a peptide hormone secreted from the white adipose tissue, may play a role in the anti-aging and/or anti-tumor effects of calorie restriction (CR). We analyzed metabolic traits in Adipoq gene-overexpressing mice fed ad libitum with a regular diet (RD) or a high-fat diet (HFD), or fed 30% CR of RD initiated at 12. weeks of age. Adipoq-RD and -HFD mice at 6. months of age showed reduced blood glucose and insulin concentrations, and thus increased insulin sensitivity, compared with WT mice fed a RD or a HFD. In the epididymal white adipose tissue in Adipoq mice, senescence-like changes such as upregulation of p53 protein and of biomarkers of inflammation, Cd68 and Ccl2 mRNA, were ameliorated compared with WT-RD and WT-HFD mouse tissues. Resistance to stress induced by lipopolysaccharide was also strengthened in Adipoq mice compared with WT mice. These metabolic changes and stress resistance were also noted in the WT-CR mice, suggesting that Adipoq plays a part in the effect of CR. In contrast, in an allograft tumor growth model, tumor growth was not inhibited in Adipoq mice. The present findings suggest that Adipoq plays a part in the anti-aging, but not in the anti-tumor, effects of CR., identifier:Experimental Gerontology, 64, pp.46-54; 2015

Published
2020

38. FoxO1 is involved in the antineoplastic effect of calorie restriction.

Author

Yamaza, Haruyoshi, Komatsu, Toshimitsu, Wakita, Saori, Kijogi, Carole, Park, Seongjoon, Hayashi, Hiroko, Chiba, Takuya, Mori, Ryoichi, Furuyama, Tatsuo, Mori, Nozomu, Shimokawa, Isao, Yamaza, Haruyoshi, Komatsu, Toshimitsu, Wakita, Saori, Kijogi, Carole, Park, Seongjoon, Hayashi, Hiroko, Chiba, Takuya, Mori, Ryoichi, Furuyama, Tatsuo, Mori, Nozomu, and Shimokawa, Isao

Abstract

The FoxO transcription factors may be involved in the antiaging effect of calorie restriction (CR) in mammals. To test the hypothesis, we used FoxO1 knockout heterozygotic (HT) mice, in which the FoxO1 mRNA level was reduced by 50%, or less, of that in wild-type (WT) mouse tissues. The WT and HT mice were fed ad libitum (AL) or 30% CR diets from 12 weeks of age. Aging- and CR-related changes in body weight, food intake, blood glucose, and insulin concentrations were similar between the WT and HT mice in the lifespan study. The response to oxidative stress, induced by intraperitoneal injection of 3-nitropropionic acid (3-NPA), was evaluated in the liver and hippocampus at 6 months of age. Several of the selected FoxO1-target genes for cell cycle arrest, DNA repair, apoptosis, and stress resistance were up-regulated in the WT-CR tissues after 3-NPA injection, while the effect was mostly diminished in the HT-CR tissues. Of these gene products, we focused on the nuclear p21 protein level in the liver and confirmed its up-regulation only in the WT-CR mice in response to oxidative stress. The lifespan did not differ significantly between the WT and HT mice in AL or CR conditions. However, the antineoplastic effect of CR, as indicated by reduced incidence of tumors at death in the WT-CR mice, was mostly abrogated in the HT-CR mice. The present results suggest a role for FoxO1 in the antineoplastic effect of CR through the induction of genes responsible for protection against oxidative and genotoxic stress., identifier:Aging cell, 9(3), pp.372-382; 2010

Published
2020

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

Author

Higami, Yoshikazu, Tsuchiya, Tomoshi, Chiba, Takuya, Yamaza, Haruyoshi, Muraoka, Izumi, Hirose, Megumi, Komatsu, Toshimitsu, and Shimokawa, Isao

Subjects
Gene expression -- Research, Rats -- Genetic aspects, Rats -- Research, Rattus -- Genetic aspects, Rattus -- Research, Lipid metabolism -- Research, Health, Seniors
Abstract

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-l-dependent manner, and those involved in lipid metabolism were regulated in a GH/IGF-l-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.

Published
2006

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

Author

Komatsu, Toshimitsu, Chiba, Takuya, Yamaza, Haruyoshi, To, Kazuo, Toyama, Hiroaki, Higami, Yoshikazu, and Shimokawa, Isao

Subjects
Gene expression -- Research, Gerontology -- Research, Hypothalamus -- Research, Rats as laboratory animals -- Research, Leptin -- Research, Health, Seniors
Abstract

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.

Published
2006

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