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KAKEN_18K15399seika.pdf
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:May 17, 2022 |
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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
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チョウカン NAMPT-NAD ゴウセイケイ オ ヒョウテキ トシタ NMN ニ ヨル インスリン テイコウセイ ヨボウホウ ノ カイハツ
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Chōkan NAMPT-NAD gōseikei o hyōteki toshita NMN ni yoru insurin teikōsei yobōhō no kaihatsu
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Therapeutic potential of intestinal epithelial NAMPT-mediated NAD+ biosynthesis in insulin resistance
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山口, 慎太郎
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ヤマグチ, シンタロウ
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Yamaguchi, Shintarō
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慶應義塾大学・医学部 (信濃町) ・助教
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Research team head
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科研費研究者番号 : 50464855
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2021
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科学研究費補助金研究成果報告書
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2020
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本研究では、腸管NAMPT-NAD+合成系の糖代謝制御における役割を検証するために、腸管上皮細胞特異的Namptノックアウトマウスを作成・解析し、腸管のNAMPT-NAD+合成系の障害が、GLP-1分泌不全、インスリン初期分泌不全および食後高血糖を惹起することを見出した。
さらに、高脂肪食誘導性肥満マウスへのNMN経口投与による腸管NAD+量の回復・上昇は、内因性GLP-1分泌を促進し、食後高血糖を改善することを見出した。
本研究で得られた知見は、NMNによる腸管NAMPT-NAD+合成系を標的とした介入が、GLP-1分泌を促進し、食後高血糖の治療法開発に繋がる可能性を示唆している。
The purpose of the present project was to test the hypothesis that intestinal NAMPT-mediated NAD+ biosynthesis plays a critical role in obesity-associated insulin resistance. To this end, we generated and analyzed intestinal epithelial cells-specific Nampt knockout mouse model, namely INKO mice.
We found that INKO mice did not exhibit insulin resistance. However, INKO had decreased production of glucagon-like peptide-1 (GLP-1), resulting in reduced early-phase insulin secretion and postprandial hyperglycemia. Importantly, nicotinamide mononucleotide (NMN), a product of NAMPT reaction, restored intestinal NAD+ levels and increased GLP-1 production in high fat diet-induced obese mice. Taken together, our results demonstrate that intestinal NAMPT-mediated NAD+ biosynthesis is essential for a normal glucoregulatory response via regulating GLP-1 production.
This work provides therapeutic insights into intestinal NAD+ biology in the obesity-associated dysregulation of glucose metabolism.
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研究種目 : 若手研究
研究期間 : 2018～2020
課題番号 : 18K15399
研究分野 : NAD合成系
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