Cited by 80Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismDiabetes, Cardiovascular Risks, and Lipoproteins

Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity

Open access
Timmers, Silvie, Nabben, Miranda, Bosma, Madeleen, van Bree, Bianca, Lenaers, Ellen, van Beurden, Denis, Schaart, Gert, Westerterp-Plantenga, Margriet S. +4 more·2012·Proceedings of the National Academy of Sciences

Abstract

A low fat oxidative capacity has been linked to muscle diacylglycerol (DAG) accumulation and insulin resistance. Alternatively, a low fat oxidation rate may stimulate glucose oxidation, thereby enhancing glucose disposal. Here, we investigated whether an ethyl-2-[6-(4-chlorophenoxy)hexyl]-oxirane-2-carboxylate (etomoxir)-induced inhibition of fat oxidation leads to muscle fat storage and insulin resistance. An intervention in healthy male subjects was combined with studies in human primary myotubes. Furthermore, muscle DAG and triacylglycerol (TAG), mitochondrial function, and insulin signaling were examined in etomoxir-treated C57bl6 mice. In humans, etomoxir administration increased glucose oxidation at the expense of fat oxidation. This effect was accompanied by an increased abundance of GLUT4 at the sarcolemma and a lowering of plasma glucose levels, indicative of improved glucose homeostasis. In mice, etomoxir injections resulted in accumulation of muscle TAG and DAG, yet improved insulin-stimulated GLUT4 translocation. Also in human myotubes, insulin signaling was improved by etomoxir, in the presence of increased intramyocellular lipid accumulation. These insulin-sensitizing effects in mice and human myotubes were accompanied by increased phosphorylation of AMP-activated protein kinase (AMPK). Our results show that a reduction in fat oxidation leading to accumulation of muscle DAG does not necessarily lead to insulin resistance, as the reduction in fat oxidation may activate AMPK.

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Crossref · 10.1073/pnas.1206868109

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Authors
Timmers, S., Nabben, M., Bosma, M., van Bree, B., Lenaers, E., van Beurden, D., Schaart, G., Westerterp-Plantenga, M. S., Langhans, W., Hesselink, M. K. C., Schrauwen-Hinderling, V. B., & Schrauwen, P.
Affiliations
  • TiFN (NL)
  • Maastricht University (NL)
  • Department of Human Biology,
  • Top Institute Food and Nutrition, 6700 AN Wageningen, The Netherlands;
  • Radiology, School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands; and
Venue
Proceedings of the National Academy of Sciences
Published
2012-07-02
Volume
109
Issue
29
Pages
11711-11716
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2016127167
Cited by
80
References
40
Citations by year
2025: 3 · 2024: 5 · 2023: 1 · 2022: 1 · 2021: 7 · 2020: 5 · 2019: 12 · 2018: 2 · 2017: 6 · 2016: 9 · 2015: 7 · 2014: 13 · 2013: 8 · 2012: 1
FWCI
3.73
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, other-oa)
  • Socio-Environmental Systems Modeling (acceptedVersion)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
insulin sensitivity, insulin resistance, triglycerides, fatty acid oxidation, etomoxir, AMPK, GLUT4 translocation, glucose oxidation, intramyocellular lipid, mitochondrial function, insulin signaling, glucose homeostasis
MeSH terms
Analysis of Variance, Animals, Diglycerides, Epoxy Compounds, Fatty Acids, Fluorescent Antibody Technique, Humans, Insulin Resistance, Male, Mice, Inbred C57BL, Mitochondria, Oxidation-Reduction, Sarcolemma, Triglycerides, Blotting, Western, Muscle Fibers, Skeletal, Glucose Transporter Type 4, Mice

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