褐色脂肪:細胞がカロリーを消費して熱を生み出す仕組み(Brown fat: how cells generate heat by burning calories)

2024-09-17

2024-09-16 ミュンヘン大学(LMU)

LMU大学病院の研究者は、ミトコンドリア内の熱産生を制御する新しいスイッチを発見しました。褐色脂肪細胞は、カロリーを燃焼して熱を生産し、体温を維持すると同時に肥満や代謝障害を防ぎます。研究チームは、褐色脂肪細胞が代謝を促進する新しいメカニズムを解明し、これが代謝疾患の治療に役立つ可能性があると期待しています。また、冷気への定期的な暴露が褐色脂肪を活性化させ、健康に良い影響を与えることも確認されました。

<関連情報>

褐色脂肪の熱発生を支えるATP合成酵素加水分解活性の寒冷制御スイッチとしてIF1が働く IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat

Henver S Brunetta, Anna S Jung , Fernando Valdivieso-Rivera , Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira , Susanne Keipert , Martin Jastroch , Laurent O Martinez , Carlos H Sponton, Roger F Castilho , Marcelo A Mori , and Alexander Bartelt
The EMBO Journal Published:16 September 2024
DOI:https://doi.org/10.1038/s44318-024-00215-0

Abstract

While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F₁Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called “reverse mode” of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.

Synopsis

How the hydrolytic activity of mitochondrial ATP synthase is modulated during brown adipose tissue (BAT) thermogenesis remains unexplored. This study demonstrates that reduction of inhibitory factor 1 (IF1) upon cold conditions facilitates the reverse mode activity of ATP synthase for bioenergetic adaptation during thermogenesis.

•IF1 depletion in mouse BAT following cold exposure increases hydrolytic activity of ATP synthase.

•IF1 overexpression in brown adipocytes impairs maintenance of the mitochondrial membrane potential upon adrenergic stimulation.

•IF1 overexpression in BAT of mice impairs non-shivering thermogenesis induced by β₃-adrenergic agonists.