The DOI matches its Crossref record; 69 of the 70 references it cites were found in a registry or an index.
Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver
Open accessAbstract
The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin resistance promotes hepatic TCA cycle flux in mice progressing to insulin resistance and fatty liver on a high-fat diet (HFD) for 32 weeks using standard biomolecular and in vivo (2)H/(13)C tracer methods. Relative mitochondrial content increased, but respiratory efficiency declined by 32 weeks of HFD. Fasting ketogenesis became unresponsive to feeding or insulin clamp, indicating blunted but constitutively active mitochondrial β-oxidation. Impaired insulin signaling was marked by elevated in vivo gluconeogenesis and anaplerotic and oxidative TCA cycle flux. The induction of TCA cycle function corresponded to the development of mitochondrial respiratory dysfunction, hepatic oxidative stress, and inflammation. Thus, the hepatic TCA cycle appears to enable mitochondrial dysfunction during insulin resistance by increasing electron deposition into an inefficient respiratory chain prone to reactive oxygen species production and by providing mitochondria-derived substrate for elevated gluconeogenesis.
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“In line with these arguments, both hepatic insulin resistance and simple steatosis were already established in mice fed a high-fat diet for 8 weeks, well before changes in mitochondrial bioenergetics became evident166,167.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [167]
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Metadata
- Authors
- Satapati, S., Sunny, N. E., Kucejova, B., Fu, X., He, T. T., Méndez-Lucas, A., Shelton, J. M., Perales, J. C., Browning, J. D., & Burgess, S. C.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Universitat de Barcelona (ES)
- Corresponding author
- Burgess, Shawn C.
- ORCID
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 53
- Issue
- 6
- Pages
- 1080-1092
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC3351815
- OpenAlex
- W2036097574
- Cited by
- 407
- References
- 70
- Citations by year
- 2026: 19 · 2025: 33 · 2024: 23 · 2023: 41 · 2022: 35 · 2021: 30 · 2020: 44 · 2019: 36 · 2018: 25 · 2017: 24 · 2016: 31 · 2015: 23 · 2014: 22 · 2013: 17 · 2012: 2
- FWCI
- 8.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK058398, R01DK087977, R01DK078184)
- National Institute of Dental and Craniofacial Research (UL1DE019584)
- National Center for Research Resources (P41RR002584, RR‐02584)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- TCA cycle, hepatic insulin resistance, high-fat diet, mitochondrial dysfunction, mitochondrial respiration, fat oxidation, ketogenesis, gluconeogenesis, oxidative stress, inflammation, insulin signaling, reactive oxygen species, mitochondrial beta-oxidation
- MeSH terms
- Animals, Citric Acid Cycle, Fatty Liver, Gluconeogenesis, Hyperglycemia, Insulin Resistance, Ketone Bodies, Liver, Male, Mice, Inbred C57BL, Mitochondria, Obesity, Time Factors, Oxidative Stress, Cell Respiration, Mice, Diet, High-Fat
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