Novel roles of insulin and adipose tissue macrophages in fat accumulation

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K19554
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: Gunma University
• Principal Investigator: Izumi Tetsuro 群馬大学, 生体調節研究所, 教授 (00212952)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Keywords: 脂肪細胞 / マクロファージ / 脂肪蓄積 / 脂肪分解

Outline of Final Research Achievements

Previous genetic studies in mice have shown that functional loss of activin receptor-like kinase 7 (ALK7) increases lipolysis to resist fat accumulation in adipocytes. However, it was unknown what kind of ALK7 ligand functions or where and how its production is regulated. Here, we show that growth/differentiation factor 3 (GDF3) is a physiological ALK7 ligand under nutrient-excess conditions, and that GDF3 is produced from adipose tissue macrophages (ATMs). Furthermore, a low level of insulin upregulates in ATMs, and directs ALK7-dependent accumulation of fat in vivo. However, depletion of ATMs or transplantation of GDF3-deficient bone marrow negates the in vivo effects of insulin on both lipolysis and fat accumulation. When this insulin-GDF3-ALK7 signaling pathway is inhibited, fat weight and serum leptin levels were markedly reduced in obese mouse models. Thus, ALK7 that targets fat accumulation is promising and robust medical intervention regardless of the cause of obesity.

Free Research Field

内分泌代謝学

Academic Significance and Societal Importance of the Research Achievements

近年、生活習慣の変化により、肥満およびそれに付随する疾患の頻度が、世界レベルで急増している。肥満の成因は、遺伝要因と後天要因（環境要因）が多角的に関与しており、原因によらない、普遍的な治療法が求められるが、有効な手段がないのが現状である。本研究では、脂肪細胞における脂肪蓄積の新奇分子機構を明らかにし、また、これを抑制することにより、少なくともマウス個体レベルにおいて肥満を大幅に軽減することができることを示した。すなわち、肥満の最終表現型である脂肪蓄積を制御することにより、原因によらない肥満治療の標的と治療効果を提示し、将来のヒト肥満症への適用が期待される。