Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, United States.
Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility, Roy J. and Lucille A. Carver College of Medicine, Iowa City, United States.
Elife. 2021 May 4;10:e66519. doi: 10.7554/eLife.66519.
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.
棕色脂肪细胞的肾上腺素刺激会改变线粒体动力学，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）生理学直接联系起来的机制尚不完全清楚。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 对于冷诱导的 BAT 产热基因的激活是必需的。出乎意料的是，OPA1 缺陷以 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的褐色化、增加静息代谢率和改善体温调节来介导适应性反应。然而，独立于 FGF21 但依赖于 ATF4 诱导的机制促进了 OPA1BATKO 小鼠对饮食诱导肥胖的抵抗。这些发现揭示了 BAT 介导的代谢保护的一种动态平衡机制，部分由 ATF4-FGF21 轴控制，该轴的激活独立于 BAT 的产热功能。
