Clarifying the role of environment-induced epigenetic change in pancreatic beta-cells in the etiology of obesity

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08496
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Osaka University (2020); National Center for Global Health and Medicine (2018-2019)
• Principal Investigator: Nammo Takao 大阪大学, 医学系研究科, 特任研究員 (50594115)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 環境因子 / エピゲノム / 膵島 / 肥満 / ２型糖尿病 / モデルマウス / インスリン分泌 / 遺伝素因

Outline of Final Research Achievements

A range of environmental factors, such as sedentary life style and overfeeding, can cause obesity, while the underlying mechanisms had not been clarified. To address this issue, we performed genome-wide epigenomic analyses of pancreatic islets derived from inbred mouse strains housed under conditions linked to weight gain. ChIP-Seq of H3K27ac, a marker of cis-elements, revealed epigenomic changes in the overweight mice relative to controls. The analyses also identified a binding motif of NRF1 as the most enriched in increased H3K27ac regions in two independent experimental models, suggesting common upstream signals. Since we found a previously uncharacterized role of NRF1 in insulin secretion from pancreatic beta-cells, it was speculated that the environment-induced epigenomic change could be involved in the etiology of obesity. Taken together, we suggest that the epigenomic modulation of beta-cells through mechanisms related to NRF1 could be a potential intervention for obesity.

Free Research Field

糖尿病学

Academic Significance and Societal Importance of the Research Achievements

肥満の臨床像は経過、合併症および内科的治療効果などの点で多様である。食事療法や運動療法に抵抗性の症例には、背景として膵β細胞の自律的な機能変化が関与する可能性を本研究は示唆している。このメカニズムに着目して研究を展開できれば、新たな観点に基づいた肥満治療法に道が拓かれる可能性がある。そして、特に難治症例について患者の負担が軽減されるとともに治療効果が向上する可能性があり、合併疾患の減少を通じて社会的にも医療費削減など重要な成果につながることが期待される。