Elucidation of the role of Pin1 in thermogenesis and temperature-dependent Pin1 degradation

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K19431
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Hiroshima University
• Principal Investigator: Asano Tomoichiro 広島大学, 医系科学研究科(医), 教授 (70242063)
• Co-Investigator(Kenkyū-buntansha): 中津 祐介 広島大学, 医系科学研究科(医), 講師 (20452584)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Keywords: Pin1 / 脂肪細胞 / 熱産生 / 肥満 / 代謝

Outline of Final Research Achievements

Non-shivering thermogenesis in adipocytes provides defense against low temperatures and obesity development, but the underlying regulatory mechanism remains to be fully clarified. Adipose-specific Pin1 KO (adPin1 KO) mice showed enhanced transcription of thermogenic genes, including UCP-1, and tolerance to hypothermia when exposed to cold (temperature at 4℃). In addition, adPin1 KO mice were resistant to high fat diet-induced obesity and glucose intolerance. Searching for Pin1 binding proteins as well as subsequent overexpression and gene silencing experiments revealed that Pin1 binds to PRDM16 and thereby promotes its degradation through the ubiquitin-proteasome system.
Taken together, these observations indicate Pin1 to be a negative regulator of non-shivering thermogenesis, which involves the regulation of thermogenesis in response to nutrient conditions and cold exposure.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

体内からの熱産生は、基礎代謝量に影響している。従って、脂肪細胞からの熱産生量の減少が、肥満や脂肪感を含めたメタボリックシンドロームの発症に影響しているが、このプロセスにPin1の発現量増加が関与していることが明らかとなった。実際、Pin1の遺伝子欠損マウスは、基礎代謝が高く、肥満に抵抗性を示す。我々は、従って、Pin1の活性を抑制する薬剤を開発し、肥満やNASHへの治療薬への応用を目指しており、社会的意義も高い。