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Gene Expression and Tracer-Based Metabolic Flux Analysis Reveals Tissue-Specific Metabolic Scaling in vitro, ex vivo, and in vivo

View ORCID ProfileNgozi D. Akingbesote, View ORCID ProfileBrooks P. Leitner, View ORCID ProfileDaniel G. Jovin, View ORCID ProfileReina Desrouleaux, Wanling Zhu, View ORCID ProfileZongyu Li, View ORCID ProfileMichael N. Pollak, View ORCID ProfileRachel J. Perry
doi: https://doi.org/10.1101/2022.03.02.482685
Ngozi D. Akingbesote
1Departments of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510
2Departments of Internal Medicine – Endocrinology, Yale School of Medicine, New Haven, CT 06510
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Brooks P. Leitner
1Departments of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510
2Departments of Internal Medicine – Endocrinology, Yale School of Medicine, New Haven, CT 06510
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Daniel G. Jovin
1Departments of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510
2Departments of Internal Medicine – Endocrinology, Yale School of Medicine, New Haven, CT 06510
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Reina Desrouleaux
1Departments of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510
3Departments of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510
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Wanling Zhu
1Departments of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510
2Departments of Internal Medicine – Endocrinology, Yale School of Medicine, New Haven, CT 06510
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Zongyu Li
1Departments of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510
2Departments of Internal Medicine – Endocrinology, Yale School of Medicine, New Haven, CT 06510
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Michael N. Pollak
4Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada
5Department of Oncology, McGill University, Montreal, QC, Canada
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Rachel J. Perry
1Departments of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510
2Departments of Internal Medicine – Endocrinology, Yale School of Medicine, New Haven, CT 06510
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  • For correspondence: rachel.perry@yale.edu
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Abstract

Metabolic scaling, the inverse correlation of metabolic rates to body mass, has been appreciated for more than 80 years. Studies of metabolic scaling have almost exclusively been restricted to mathematical modeling of oxygen consumption. The possibility that other metabolic processes scale with body size has not been studied. To address this gap in knowledge, we employed a systems approach spanning from transcriptomics to in vitro and in vivo tracer-based flux. Gene expression in livers of five species spanning a 30,000-fold range in mass revealed differential expression of genes related to cytosolic and mitochondrial metabolic processes, in addition to detoxication of oxidative damage. This suggests that transcriptional scaling of damage control mechanisms accommodates increased oxidative metabolism in smaller species. To determine whether flux through key implicated metabolic pathways scaled, we applied stable isotope tracer methodology to study multiple cellular compartments, tissues, and species. Comparing mice and rats, we demonstrate that while scaling of metabolic fluxes is not observed in the cell-autonomous setting, it is present in liver slices and in vivo. Together, these data reveal that metabolic scaling extends beyond oxygen consumption to numerous other metabolic pathways, and is likely regulated at the level of gene expression and substrate supply.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 04, 2022.
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Gene Expression and Tracer-Based Metabolic Flux Analysis Reveals Tissue-Specific Metabolic Scaling in vitro, ex vivo, and in vivo
Ngozi D. Akingbesote, Brooks P. Leitner, Daniel G. Jovin, Reina Desrouleaux, Wanling Zhu, Zongyu Li, Michael N. Pollak, Rachel J. Perry
bioRxiv 2022.03.02.482685; doi: https://doi.org/10.1101/2022.03.02.482685
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Gene Expression and Tracer-Based Metabolic Flux Analysis Reveals Tissue-Specific Metabolic Scaling in vitro, ex vivo, and in vivo
Ngozi D. Akingbesote, Brooks P. Leitner, Daniel G. Jovin, Reina Desrouleaux, Wanling Zhu, Zongyu Li, Michael N. Pollak, Rachel J. Perry
bioRxiv 2022.03.02.482685; doi: https://doi.org/10.1101/2022.03.02.482685

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