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A Fluxomics Approach Toward Quantifying the Metabolic Response to Cold Stress / Marc R Bornstein.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Bornstein, Marc R., author.
- Language:
- English
- Subjects (All):
- Physiology.
- Cellular biology.
- Molecular biology.
- Developmental biology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Physiology.
- Cellular biology.
- Molecular biology.
- Developmental biology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (133 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Contained In:
- Dissertations Abstracts International 85-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- Cold-induced thermogenesis (CIT) is widely studied as a potential avenue to treat obesity and metabolic disease. However, a thorough understanding of how systemic metabolism changes during CIT is lacking. Here, we present a comprehensive, quantitative analysis of the murine metabolic response to acute cold exposure. Metabolomic profiling of arterial plasma from unanesthetized fasting mice undergoing CIT identified changes in hundreds of metabolites, both known and novel. Profiling of various organs revealed widespread cold-induced metabolic changes, not limited to canonically thermogenic organs like brown adipose tissue (BAT). Minimally perturbative stable isotope-tracing infusion studies allowed for quantitative flux measurements in both fasting and ad libitum fed mice, revealing increased whole-body circulatory flux of a variety of nutrients. Fatty acid flux accounted almost entirely for the cold-induced elevation of metabolic rate during fasting, and BAT greatly increased its preference for circulating fatty acid oxidation during CIT. In contrast, systemic carbohydrate flux predominated in the fed state, and BAT increased its preference for glucose use in response to cold, indicating that BAT is flexible in its choice of fuels. Skeletal muscle increased its preference for oxidation of branched chain amino acids (BCAAs) and ketone bodies during CIT in both fed and fasted animals, while BAT consumed minimal amounts of these nutrients. Elevated glucose flux stemmed largely from dietary carbohydrates in fed mice and from gluconeogenesis in fasted mice, with minimal contribution from glycogen. Studies with genetically modified mice revealed that cold-induced gluconeogenic flux, despite being minimal compared to circulatory flux of fatty acids in fasted animals, is critical for cold tolerance. While much of the cold-induced glucose disposal feeds lactate production, a substantial portion contributes carbons to the TCA cycle in several tissues including BAT. Surprisingly, isotopic labeling of TCA cycle intermediates revealed that, unlike other tissues, BAT uses glucose-derived mitochondrial pyruvate largely for TCA anaplerotic flux via carboxylation. Together, these findings provide a detailed and quantitative map of the metabolic changes that drive acute CIT, identify distinct uses for key nutrients that fuel the thermogenic response, and unveil a critical role for gluconeogenic flux during CIT.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Arany, Zoltan; Committee members: Simon, M. Celeste; Baur, Joseph A.; Titchenell, Paul; Seale, Patrick.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381471298
- Access Restriction:
- Restricted for use by site license.
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