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Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance

Abstract

Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C ε activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.

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Figure 1: Targeting of the Elovl6 gene.
Figure 2: Body weight, adiposity and glucose homeostasis in wild-type and Elovl6−/− mice fed a standard chow or HF-HS diet.
Figure 3: Protection from diet-induced insulin resistance in the absence of Elovl6.
Figure 4: Effects of Elovl6 deficiency on mRNA and protein levels and fatty acid metabolism in the livers of wild-type and Elovl6−/− mice fed a regular chow or HF-HS diet.
Figure 5: Effects of hepatic Elovl6 expression on gene expression, fatty acid metabolism and insulin sensitivity.
Figure 6: The effects of Elovl6 overexpression and palmitate/palmitoleate ratio on Hepa1c1c7 hepatoma cells and of Elovl6 deficiency on genetically obese mice.

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Acknowledgements

We thank T. Ide and H. Daitoku for technical help and/or useful comments. This work was supported by grants-in-aid from the Ministry of Science, Education, Culture and Technology of Japan; a grant for the Japan Foundation for Applied Enzymology; and a grant from The Naito Foundation.

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Contributions

T. Matsuzaka carried out most of the experiments, data analysis and prepared the figures with significant help from M.I., S.O., N. Ishigaki, H.I., Y.I. and T. Karasawa. H. Shimano developed the idea for and supervised the study, designed protocols, developed collaborations and wrote the manuscript. N. Yahagi contributed to many in vivo experiments and to training T. Matsuzaka in experimental techniques. T. Kato carried out measurements of fatty acid composition and assisted with hepatocyte isolations, fatty acid treatment to the cell and mice and adenoviral experiments. A.A. assisted with the in vivo adenoviral experiments. T.Y. assisted with PKCε analysis and cell-line experiments. N. Inoue assisted with ELISA measurements and developed the DXA protocols for analyzing fat. S.K. assisted with RT-PCR analysis. T. Matsui contributed to primary myotube culture and the 2-DG uptake assay. M.S. and K.O. participated in the experimental design and in training T. Matsuzaka in experimental techniques. A.H.H. reviewed the manuscript. Y.N. contributed to immunoblot analysis of insulin signaling, adenoviral work and discussion of the results. A.T. contributed to GTT, ITT, HF-HS diet–feeding to the mice and discussion of the results. H. Suzuki, S.Y., H. Sone, H.T. and J.O. contributed to experimental design, data analysis, interpretation and presentation. N. Yamada supervised the study, contributed crucial ideas to the project and reviewed the manuscript.

Corresponding author

Correspondence to Hitoshi Shimano.

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Matsuzaka, T., Shimano, H., Yahagi, N. et al. Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance. Nat Med 13, 1193–1202 (2007). https://doi.org/10.1038/nm1662

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