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

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 systemi...

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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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS IHJ, ADM, YZ, BBQ, AMB conceived the project and performed the experiments. IHJ, ADM, YZ designed the experiments and analyzed the data. ADM, IHJ wrote the manuscript. COYF, JEB prepared PET radiotracers. BTLC and AGH assisted with tissue PO2 measurements. HV, YS designed PET radiotracers and assisted with data analysis.
ISSN:	1550-4131 1932-7420
DOI:	10.1016/j.cmet.2023.02.007