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Cited by 91Liver Disease Diagnosis and TreatmentMetabolism, Diabetes, and CancerDiet, Metabolism, and Disease

Enhancing liver mitochondrial fatty acid oxidation capacity in obese mice improves insulin sensitivity independently of hepatic steatosis

Monsénégo, Julia, Mansouri, Abdelhak, Akkaoui, Marie, Lenoir, Véronique, Esnous, Catherine, Fauveau, Véronique, Tavernier, Valentin, Girard, Jean +1 more·2012·Journal of Hepatology
DOI 10.1016/j.jhep.2011.10.008
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Abstract

Background & aims Despite major public health concern, therapy for non-alcoholic fatty liver, the liver manifestation of the metabolic syndrome often associated with insulin resistance (IR), remains elusive. Strategies aiming to decrease liver lipogenesis effectively corrected hepatic steatosis and IR in obese animals. However, they also indirectly increased mitochondrial long-chain fatty acid oxidation (mFAO) by decreasing malonyl-CoA, a lipogenic intermediate, which is the allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT1A), the key enzyme of mFAO. We thus addressed whether enhancing hepatic mFAO capacity, through a direct modulation of liver CPT1A/malonyl-CoA partnership, can reverse an already established hepatic steatosis and IR in obese mice.Methods Adenovirus-mediated liver expression of a malonyl-CoA-insensitive CPT1A (CPT1mt) in high-fat/high-sucrose (HF/HS) diet-induced or genetically (ob/ob) obese mice was followed by metabolic and physiological investigations.Results In association with increased hepatic mFAO capacity, liver CPT1mt expression improved glucose tolerance and insulin response to a glucose load in HF/HS and ob/ob mice, showing increased insulin sensitivity, and corrected IR in ob/ob mice. Surprisingly, hepatic steatosis was not affected in CPT1mt-expressing obese mice, indicating a clear dissociation between hepatic steatosis and IR. Moreover, liver CPT1mt expression rescued HF/HS-induced impaired hepatic insulin signaling at the level of IRS-1, IRS-2, Akt, and GSK-3β, most likely through the observed decrease in the HF/HS-induced accumulation of lipotoxic lipids, oxidative stress, and JNK activation.Conclusions Enhancing hepatic mFAO capacity is sufficient to reverse a state of IR and glucose intolerance in obese mice independently of hepatic steatosis.

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  • In these studies, enhanced mitochondrial FAO did not increase ROS derivatives or liver injury.

    “Furthermore, in these studies, enhanced mitochondrial FAO did not increase ROS derivatives or liver injury.”

    From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [117]

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Authors
Monsénégo, J., Mansouri, A., Akkaoui, M., Lenoir, V., Esnous, C., Fauveau, V., Tavernier, V., Girard, J., & Prip-Buus, C.
Affiliations
Centre National de la Recherche Scientifique (FR)
ORCID
Mansouri, Abdelhak
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2012-03
Volume
56
Issue
3
Pages
632-639
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2011.10.008
OpenAlex
W1983167131
Cited by
91
References
38
Citations by year
2026: 2 · 2025: 5 · 2024: 9 · 2023: 8 · 2022: 4 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 9 · 2017: 4 · 2016: 7 · 2015: 10 · 2014: 9 · 2013: 6 · 2012: 6
FWCI
5.03
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Keywords
mitochondrial fatty acid oxidation, carnitine palmitoyltransferase 1, malonyl-CoA, insulin resistance, hepatic steatosis, non-alcoholic fatty liver disease, obesity, glucose tolerance, insulin signaling, oxidative stress, JNK activation, adenoviral gene transfer, high-fat diet, ob/ob mice
MeSH terms
Adenoviridae, Animals, Body Weight, Carnitine O-Palmitoyltransferase, Fatty Acids, Fatty Liver, Glucaric Acid, Insulin Resistance, Male, Malonyl Coenzyme A, Mice, Inbred C57BL, Mice, Obese, Mitochondria, Liver, Obesity, Oxidation-Reduction, Glucose Intolerance, Adiposity, Lipid Metabolism, Mice

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