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Lipid-mediated muscle insulin resistance: different fat, different pathways?

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Abstract

Increased dietary fat intake and lipolysis result in excessive lipid availability, which relates to impaired insulin sensitivity. Over the last years, several mechanisms possibly underlying lipid-mediated insulin resistance evolved. Lipid intermediates such as diacylglycerols (DAG) associate with changes in insulin sensitivity in many models. DAG activate novel protein kinase C (PKC) isoforms followed by inhibitory serine phosphorylation of insulin receptor substrate 1 (IRS1). Activation of Toll-like receptor 4 (TLR4) raises another lipid class, ceramides (CER), which induce pro-inflammatory pathways and lead to inhibition of Akt phosphorylation. Inhibition of glucosylceramide and ganglioside synthesis results in improved insulin sensitivity and increased activatory tyrosine phosphorylation of IRS1 in the muscle. Incomplete fat oxidation can increase acylcarnitines (ACC), which in turn stimulate pro-inflammatory pathways. This review analyzed the effects of lipid metabolites on insulin action in skeletal muscle of humans and rodents. Despite the evidence for the association of both DAG and CER with insulin resistance, its causal relevance may differ depending on the subcellular localization and the tested cohorts, e.g., athletes. Nevertheless, recent data indicate that individual lipid species and their degree of fatty acid saturation, particularly membrane and cytosolic C18:2 DAG, specifically activate PKCθ and induce both acute lipid-induced and chronic insulin resistance in humans.

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Acknowledgments

The authors’ work is supported by the Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW), the German Federal Ministry of Health (BMG) and by grants of the Federal Ministry for Research (BMBF) to the German Center for Diabetes Research (DZD e.V.), the Helmholtz Alliance with Universities (Imaging and Curing Environmental Metabolic Diseases, ICEMED), the German Research Foundation (DFG; SFB 1116, B05) and the Schmutzler Stiftung, Germany. O.R. was supported by the research training group VIVID of Heinrich-Heine-University.

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The authors declare no conflict of interests.

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Authors and Affiliations

  1. Institute for Clinical Diabetology, German Diabetes Center, c/o Auf’m Hennekamp 65, D-40225, Düsseldorf, Germany

    Olesja Ritter, Tomas Jelenik & Michael Roden

  2. Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University Düsseldorf, D-40225, Düsseldorf, Germany

    Michael Roden

  3. German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany

    Tomas Jelenik & Michael Roden

Authors
  1. Olesja Ritter
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  2. Tomas Jelenik
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  3. Michael Roden
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Correspondence to Michael Roden.

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Ritter, O., Jelenik, T. & Roden, M. Lipid-mediated muscle insulin resistance: different fat, different pathways?. J Mol Med 93, 831–843 (2015). https://doi.org/10.1007/s00109-015-1310-2

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  • DOI: https://doi.org/10.1007/s00109-015-1310-2

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