New role of natriuretic peptide in energy metabolism regulation and its therapeutic potential through interorgan metabolic crosstalk

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08435
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Nagoshi Tomohisa 東京慈恵会医科大学, 医学部, 准教授 (60408432)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ナトリウム利尿ペプチド / 心臓エネルギー代謝 / インスリン抵抗性 / 生体温度制御 / 心臓脂肪連関

Outline of Final Research Achievements

Growing evidence suggests natriuretic peptides (NPs) regulate energy metabolism and exert thermogenic actions via interorgan metabolic crosstalk with adipose tissues. In vivo experiments using mice fed a high fat diet (HFD) showed ANP-treatment ameliorated HFD-induced systemic insulin resistance (IR) by activating brown adipose tissue. ANP also ameliorated myocardial IR. Ultrastructural analyses showed increased peri-mitochondrial lipid droplets in ANP-treated HFD hearts, indicating ANP protects mitochondria from lipid overload by trapping lipids. Meanwhile, we found ANP-treated mice were tolerant to cold exposure. Accordingly, our clinical study showed impaired cardiac function is associated with body temperature (BT) decrease, whereas plasma BNP elevation is associated with BT increase. In summary, exogenous ANP administration ameliorates HFD-induced systemic and myocardial IR by coordinating with adipose tissues, leading to in vivo thermogenesis during cold exposure.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

NPが特に低温環境下において保温効果を発揮したり、肥満/IR病態においてIRを改善し、心不全の病態生理の根幹であるエネルギー代謝障害に対して有利に働くことを、基礎と臨床の両面から示した。肥満や重症心不全時などIR病態では、本来ならNPが必要な病態であるにもかかわらず、実際には量的にも質的にも充分な効果を発揮していないことが示されており、こうした病態でNP補充療法の重要性・意義がより一層増すと考えられた。反対に、重症心不全に伴うcachexia状態においては、NPが作用し効を奏するために必要な脂肪組織や骨格筋量が低下し、IR改善や保温効果を十分に発揮できない可能性も明らかとなった。