エネルギーとグルコースホメオスタスのレプチン神経回路の遺伝的識別

Jie Xu¹, Christopher L Bartolome^1,2, Cho Shing Low^1,3

¹Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.

Nature

|April 20, 2018

まとめ

レプチン

科学分野:

神経科学
内分泌学
代謝に関する研究

背景:

レプチンは食欲,エネルギー消費,およびグルコースの安定性を調節しますが,神経回路の不完全な理解によって臨床応用が制限されています.
仮説的なレプチン標的であるアグウチ関連ペプチド (AGRP) とプロオピオメラノコルチン (POMC) のニューロンは,レプチンのインビボ効果を完全に説明していない.
AGRPまたはPOMCニューロンの選択的なレプチン受容体 (LEPR) 消去を用いた以前の研究では,レプチン欠乏症のフェノタイプを完全に複製することができなかった.

研究の目的:

レプチンに反応する神経細胞を体系的に特定し,レプチンの主要な神経標的を明確にする.
AGRPとPOMCニューロンのエネルギーバランスとグルコースホメオスタシスのレプチンの調節における役割を調査する.
標的ニューロンに対するレプチンの急性および慢性作用の仕組みを解明する.

主な方法:

ストレプトゾトシン誘発糖尿病マウスにおけるレプチン反応性ニューロンの体系的,偏見のない調査.
CRISPR-Cas9によるLEPRの遺伝子消去 in vivo
AGRPニューロンの化学的操作

主要な成果:

AGRPニューロンは,POMCニューロンではなく,レプチンのエネルギーバランスとグルコースホメオスタシスの調節に不可欠です.
レプチンの欠乏はAGRPニューロンを除き,これらのニューロンを阻害すると,糖尿病性高食症と高血糖症が逆転する.
AGRPニューロンのCRISPR媒介によるLEPR消去は,Lepr^db/dbマウスで見られた重度の肥満と糖尿病を正確に複製します.
レプチンは,AGRPニューロンの急性 (前シナプスGABA増強) と慢性 (後シナプスATP感受性カリウムチャネル活性化) の抑制に異なるメカニズムを使用します.

結論:

AGRPニューロンは,代謝調節のためのレプチンの主要な直接的な神経標的です.
この研究は,レプチンの主要な神経標的についての長年の疑問を解決し,代謝障害におけるその役割を明らかにします.
発見は,レプチンの作用と関連する代謝疾患の神経生物学的な基礎を提供し,将来の治療戦略の道を開きます.

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