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脂肪細胞特異的C-C motif ligand 19過剰発現マウスではインスリン抵抗性および体重増大が引き起こされる

林, 大翔 HAYASHI, Masato ハヤシ, マサト 九州大学

2021.09.24

概要

アジア人は欧米人と比べて著明な肥満こそ少ないものの、糖尿病などの代謝障害の罹患率が欧米人と同程度に高いという特徴がある。近年では生活様式の西洋化に伴い、アジア人においても肥満人口は増大傾向にあるが、大部分は欧米における過体重レベルである。つまり、アジア人は脂肪組織が少し成熟するだけで糖尿病に対する感受性が亢進すると考えられる。成熟脂肪組織では活性化免疫細胞の浸潤、および免疫細胞のリクルートに関与するC-C motif ligand 19(CCL19)等のケモカインや種々のサイトカインの発現が亢進するが、脂肪組織におけるCCL19の役割は明らかではない。本研究では、脂肪細胞特異的にCCL19を高発現させたCcl19 knock-in(Ccl19KI)マウスを作製しCCL19が脂肪組織炎症、脂質代謝に及ぼす作用について解析した。各遺伝子型マウスに、通常食、西洋食を模した40%高脂肪食(40%FD)または通常の食餌誘導性肥満マウスの実験に用いられる60%高脂肪食(60%FD)を負荷し、肥満度による影響を検討した。

 Ccl19KIマウスでは、野生型(WT)マウスに比べ脂肪組織における炎症促進シグナルの活性化と、皮下・褐色脂肪組織の増大を示した。また、Ccl19KIマウスでは、WTに比べ皮下・内臓および褐色脂肪組織におけるERK1/2のリン酸化亢進とAMPKαのリン酸化抑制、褐色脂肪組織におけるUCP1発現抑制がみられた。Ccl19KIマウスとWTマウス間でのこれらの違いは、通常食群および60%FD群間に比べ、通常食群と40%FD群間においてより顕著であった。

 以上の結果から、肥満脂肪組織におけるCCL19-CCR7経路の活性化が脂肪組織の炎症を増幅し、ERK1/2活性化を介したAMPKα抑制により脂質代謝、エネルギー制御機能の減弱を引き起こすことが示された。さらに、40%高脂肪食がこれらの変化を増強し、軽度肥満による病態の増悪が示された。本研究結果は、CCL19を標的とした代謝障害の新たな治療法確立、およびアジア人のような軽度肥満における代謝異常の病態解明につながる可能性を示すものである。

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