Organ-specific fuel rewiring in acute and chronic hypoxia redistributes glucose and fatty acid metabolism

• Published in: Cell metabolism Vol. 35; no. 3; pp. 504 - 516.e5
• Main Authors: Midha, Ayush D., Zhou, Yuyin, Queliconi, Bruno B., Barrios, Alec M., Haribowo, Augustinus G., Chew, Brandon T.L., Fong, Cyril O.Y., Blecha, Joseph E., VanBrocklin, Henry, Seo, Youngho, Jain, Isha H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.03.2023
• Subjects: fatty acid metabolism; Fatty Acids - metabolism; fuel rewiring; fuel uptake; Glucose - metabolism; Humans; hypoxia; Hypoxia - metabolism; isotope tracing; Muscle, Skeletal - metabolism; organ-specific metabolism; Oxygen - metabolism; PET scan; TCA cycle; hypoxia; fuel uptake; PET scan; fatty acid metabolism; TCA cycle; isotope tracing; organ-specific metabolism; fuel rewiring; glucose metabolism
• ISSN: 1550-4131; 1932-7420
• 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. [Display omitted] •Mice exposed to hypoxia recovered locomotor deficits over 3 weeks•Adaptation to hypoxia coincided with reduced blood glucose and adiposity•Acute hypoxia promoted glucose uptake in most organs, except brown fat and muscle•Chronic hypoxia caused organ-level rewiring of glucose and fatty acid metabolism Midha et al. show that functional adaptation to hypoxia is accompanied by organ-specific metabolic rewiring. Acute hypoxia promotes glucose uptake in most organs while reducing oxygen-consuming glucose oxidation. Chronic hypoxia promotes fatty acid metabolism in the brain, liver, and kidney while increasing glucose oxidation in the heart.