Gladstone Institutes, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA; Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
Gladstone Institutes, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Cell Metab. 2023 Mar 7;35(3):504-516.e5. doi: 10.1016/j.cmet.2023.02.007.
Oxygen deprivation can be detrimental. However, chronic hypoxia is also associated with decreased incidence of metabolic syndrome and cardiovascular disease in high-altitude populations. Previously, hypoxic fuel rewiring has primarily been studied in immortalized cells. Here, we describe how systemic hypoxia rewires fuel metabolism to optimize whole-body adaptation. Acclimatization to hypoxia coincided with dramatically lower blood glucose and adiposity. Using in vivo fuel uptake and flux measurements, we found that organs partitioned fuels differently during hypoxia adaption. Acutely, most organs increased glucose uptake and suppressed aerobic glucose oxidation, consistent with previous in vitro investigations. In contrast, brown adipose tissue and skeletal muscle became "glucose savers," suppressing glucose uptake by 3-5-fold. Interestingly, chronic hypoxia produced distinct patterns: the heart relied increasingly on glucose oxidation, and unexpectedly, the brain, kidney, and liver increased fatty acid uptake and oxidation. Hypoxia-induced metabolic plasticity carries therapeutic implications for chronic metabolic diseases and acute hypoxic injuries.
缺氧会造成损害。然而，慢性缺氧也与高原人群中代谢综合征和心血管疾病发病率降低有关。以前，缺氧燃料重编程主要在永生化细胞中进行研究。在这里，我们描述了全身缺氧如何重新编程燃料代谢以优化全身适应。低氧适应伴随着血糖和肥胖显著降低。使用体内燃料摄取和通量测量，我们发现器官在低氧适应过程中对燃料的分配不同。急性缺氧时，大多数器官增加葡萄糖摄取并抑制有氧葡萄糖氧化，这与之前的体外研究一致。相比之下，棕色脂肪组织和骨骼肌成为“葡萄糖节约器”，葡萄糖摄取减少 3-5 倍。有趣的是，慢性缺氧产生了不同的模式：心脏越来越依赖于葡萄糖氧化，出乎意料的是，大脑、肾脏和肝脏增加了脂肪酸的摄取和氧化。缺氧诱导的代谢可塑性对慢性代谢性疾病和急性缺氧性损伤具有治疗意义。
