PDF(Pubmed)
Abstract：
Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, which is activated independently of BAT thermogenic function.
摘要：
棕色脂肪细胞的肾上腺素能刺激改变线粒体动力学，包括线粒体融合蛋白视神经萎缩1(OPA1)。然而,将OPA1与棕色脂肪组织（BAT）生理学联系起来的直接机制尚不完全清楚。我们利用BAT中选择性OPA1缺失的小鼠模型（OPA1BATKO）来研究OPA1在产热中的作用。OPA1是冷诱导的BAT产热基因激活所必需的。出乎意料的是,OPA1缺陷以激活转录因子4（ATF4）依赖性方式诱导成纤维细胞生长因子21（FGF21）作为BATokine。BAT衍生的FGF21通过诱导白色脂肪组织褐变来介导适应性反应，增加静息代谢率，改善体温调节。然而,机制独立于FGF21，但依赖于ATF4诱导，促进OPA1BATKO小鼠对饮食诱导的肥胖的抵抗力。这些发现揭示了BAT介导的代谢保护的稳态机制，部分由ATF4-FGF21轴控制。它独立于BAT产热功能而被激活。
