NAD mediated mechanism of adipocyte differentiation through epigenetics

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16193
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: University of Toyama
• Principal Investigator: Okabe Keisuke 富山大学, 附属病院, 客員講師 (00770702)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: NAD / αケトグルタル酸 / 脱メチル化 / 脂肪細胞分化 / 肥満症 / エピゲノム

Outline of Final Research Achievements

Obesity has become a serious problem in public health worldwide. It causes the inflammation in adipose tissue and systemic metabolic disorders. Intracellular metabolic state changes during cell differentiation and it affects the cell fate or the differentiation through epigenetic mechanism. However, it is unknown how metabolic state changes and how it affects in preadipocyte differentiation. In this study, we conducted targeted metabolomics to elucidate the metabolic reprogramming events that occur during 3T3-L1 preadipocyte differentiation. We found that the tricarboxylic acid (TCA) cycle was enhanced, which correlated with upregulated NAD synthesis. Additionally, increased alpha-ketoglutarate (αKG) contributed to histone H3K9 demethylation in the promoter region of PPARγ, leading to its transcriptional activation. Thus, we concluded that NAD-centered metabolic reprograming is necessary for the differentiation of 3T3-L1 preadipocytes.

Free Research Field

内分泌・代謝

Academic Significance and Societal Importance of the Research Achievements

本研究により脂肪細胞分化に伴う細胞内代謝の変化が、分化の単なる結果ではなく、エピゲノムを介して分化を制御していることが明らかとなった。これは、“代謝”や“エピゲノム”が肥満症や肥満に関連する代謝疾患の治療標的となりうることを示しており、当該分野における新薬開発につながる可能性がある。