山口　慎太郎 （ヤマグチ　シンタロウ）

Yamaguchi, Shintaro

写真a

所属（所属キャンパス）

医学部 医学教育統轄センター （信濃町）

職名

准教授（有期）
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経歴 【 表示 ／ 非表示 】

  • 1999年04月
    -
    2005年03月

    慶應義塾大学医学部

  • 2009年04月
    -
    2013年03月

    慶應義塾大学 医学研究科大学院博士課程 伊藤裕教授

  • 2014年10月
    -
    2017年03月

    米国ワシントン大学医学部内科　博士研究員　吉野純博士

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学歴 【 表示 ／ 非表示 】

  • 2005年03月

    慶應義塾大学, 医学部

    卒業

  • 2013年03月

    慶應義塾大学, 医学研究科大学院博士課程

    卒業

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学位 【 表示 ／ 非表示 】

  • 医学博士, 慶應義塾大学, 2013年03月

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免許・資格 【 表示 ／ 非表示 】

  • 日本内科学会総合内科専門医・指導医, 2008年

  • 日本腎臓学会専門医・指導医, 2013年

  • 日本内分泌学会専門医, 2017年

  • 日本透析医学会専門医

  • 日本糖尿病学会専門医, 2023年12月

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研究分野 【 表示 ／ 非表示 】

  • ライフサイエンス / 代謝、内分泌学 （インスリン抵抗性、NAD合成系）

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論文 【 表示 ／ 非表示 】

  • Adipose tissue NAD<sup>+</sup> biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice

    Yamaguchi S., Franczyk M.P., Chondronikola M., Qi N., Gunawardana S.C., Stromsdorfer K.L., Porter L.C., Wozniak D.F., Sasaki Y., Rensing N., Wong M., Piston D.W., Klein S., Yoshino J.

    Proceedings of the National Academy of Sciences of the United States of America （Proceedings of the National Academy of Sciences of the United States of America）  116 （ 47 ） 23822 - 23828 2019年11月

    研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り,  ISSN  00278424

    　概要を見る

    © 2019 National Academy of Sciences. All rights reserved. Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD+ metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD+ biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD+–SIRT1–caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD+ synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD+ biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

  • Intestinal epithelial NAD + biosynthesis regulates GLP-1 production and postprandial glucose metabolism in mice.

    Nagahisa T, Yamaguchi S, Kosugi S, Homma K, Miyashita K, Irie J, Yoshino J, Itoh H

    Endocrinology 163 （ 4 ）  2022年02月

    責任著者, 査読有り,  ISSN  0013-7227

    　概要を見る

    Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.

  • Diurnal variation in PDK4 expression is associated with plasma free fatty acid availability in people

    Yamaguchi S., Moseley A., Valdes P., Stromsdorfer K., Franczyk M., Okunade A., Patterson B., Klein S., Yoshino J.

    Journal of Clinical Endocrinology and Metabolism （Journal of Clinical Endocrinology and Metabolism）  103 （ 3 ） 1068 - 1076 2018年03月

    研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り,  ISSN  0021972X

    　概要を見る

    Copyright © 2018 Endocrine Society. Context: Many biological pathways involved in regulating substrate metabolism display rhythmic oscillation patterns. In rodents, clock genes regulate circadian rhythms of metabolic genes and substrate metabolism. However, the interrelationships among substrate metabolism, metabolic genes, and clock genes have not been fully explored in people. Objective: We tested the hypothesis that the diurnal expression pattern of pyruvate dehydrogenase kinase 4 (PDK4), a key metabolic enzyme involved in fuel switching between glucose and free fatty acids (FFAs), is associated with plasma FFA concentration and clock genes. Design and Methods: We analyzed peripheral blood mononuclear cells (PBMCs), subcutaneous adipose tissue, and plasma samples obtained serially during 24 hours from metabolically healthy women (n = 10) and evaluated the interrelationships among PDK4, plasma FFA, and clock genes. We also determined the potential mechanisms responsible for PDK4 transcriptional regulation by using primary human PBMCs and adipocytes. Results: We found that PDK4 diurnal expression patterns were similar in PBMCs and adipose tissue (r = 0.84, P, 0.001). The diurnal variation in PBMC PDK4 expression correlated more strongly with plasma FFA and insulin (r 5 0.86 and 0.63, respectively, both P, 0.001) concentrations than clock genes. Data obtained from primary culture experiments demonstrated that FFAs directly induced PDK4 gene expression, at least in part through activation of peroxisome proliferator-activated receptor a. Conclusions: Our results suggest that plasma FFA availability is an important regulator of diurnal expression patterns of PDK4, and we identify a novel interaction between plasma FFA and cellular diurnal rhythms in regulating substrate metabolism.

  • Adipose tissue NAD(+) biology in obesity and insulin resistance: From mechanism to therapy

    Shintaro Yamaguchi, Jun Yoshino

    BIOESSAYS 39 （ 5 ）  2017年05月

    研究論文（学術雑誌）, 共著, 筆頭著者,  ISSN  0265-9247

    　概要を見る

    Nicotinamide adenine dinucleotide (NAD(+) ) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD(+) biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT-mediated NAD(+) biosynthesis, together with its key downstream mediator, namely the NAD(+) -dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue-dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT-mediated NAD(+) biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD(+) biology.

  • NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

    Stromsdorfer, Kelly L., Yamaguchi, Shintaro*(*Co-first author), Yoon, Myeong Jin, Moseley, Anna C., Franczyk, Michael P., Kelly, Shannon C., Qi, Nathan, Imai, Shin-ichiro, Yoshino, Jun

    CELL REPORTS 16 （ 7 ） 1851 - 1860 2016年08月

    研究論文（学術雑誌）, 共著, 筆頭著者,  ISSN  2211-1247

    　概要を見る

    Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD(+) biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adipose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. These deleterious alterations were normalized by administering rosiglitazone or a key NAD(+) intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance.

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総説・解説等 【 表示 ／ 非表示 】

  • 老化関連疾患における NAD⁺合成系・ミトコン ドリアサーチュン SIRT3 の生理学的重要性と治療標的としての可能性.

    山口慎太郎、吉野純

    日本臨床  2016年

    記事・総説・解説・論説等（学術雑誌）, 共著

  • ヒトにおける概日リズムとインスリン感受性制 御機構のクロストーク.

    山口慎太郎、吉野純

     2016年

    記事・総説・解説・論説等（学術雑誌）, 共著

  • 老化関連疾患におけるNAD+合成系の役割と創薬標的としての可能性

    山口 慎太郎，吉野 純

    生化学  2015年

    記事・総説・解説・論説等（学術雑誌）, 共著

  • 6年次臨床実習終了後に行ったプロフェッショナリズムの自己評価と同僚評価の現状とその乖離の検討

    山口 慎太郎, 春田 淳志, 門川 俊明

    医学教育 （(一社)日本医学教育学会）  55 （ Suppl. ） 245 - 245 2024年07月

    ISSN  0386-9644

  • 原発性アルドステロン症における腎洞脂肪蓄積の臨床的意義の検証

    満野 竜ノ介, 金子 賢司, 中村 俊文, 児島 大輝, 水谷 洋佑, 畔上 達彦, 山口 慎太郎, 山田 祥岳, 陣崎 雅弘, 木内 謙一郎, 吉野 純, 林 香

    日本腎臓学会誌 （(一社)日本腎臓学会）  66 （ 4 ） 629 - 629 2024年06月

    ISSN  0385-2385

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • 脂肪組織血管新生能を標的とした血管内皮NAD賦活化による肥満2型糖尿病発症予防

    2021年04月
    -
    2025年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 山口 慎太郎, 基盤研究(C), 補助金,  研究代表者

  • 腸管NAMPT-NAD合成系を標的としたNMNによるインスリン抵抗性予防法の開発

    2018年04月
    -
    2021年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 山口　慎太郎, 若手研究, 補助金,  研究代表者

  • ヒトES・iPS細胞由来腎臓・血管前駆細胞と脱細胞化技術の融合による新規腎臓再生

    2014年04月
    -
    2016年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 山口 慎太郎, 若手研究(B), 補助金, 研究代表者, 未設定

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