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Animal Models

Exogenous administration of DLK1 ameliorates hepatic steatosis and regulates gluconeogenesis via activation of AMPK

International Journal of Obesity volume 40, pages 356–365 (2016)Cite this article

Subjects

Abstract

Background/Objectives:

Activation of Notch signaling pathologically enhances lipogenesis and gluconeogenesis in the liver causing non-alcoholic fatty liver disease (NAFLD) and diabetes. Delta-like 1 homolog (DLK1), an imprinted gene that can modulate adipogenesis and muscle development in mice, was found as an inhibitory regulator of Notch signaling. Therefore, we investigated the metabolic effect of exogenous DLK1 in vitro and in vivo.

Subjects/Methods:

A soluble DLK1 peptide was generated with fusion between a human Fc fragment and extracellular domain of DLK1. Male db/db mice were randomly assigned to two groups: vehicle treated and DLK1-treated group (25 mg kg−1, intraperitoneal injection, twice a week for 4 weeks). Primary mice hepatocytes and HepG2 cells were used for in vitro experiments.

Results:

After 4 weeks of DLK1 administration, hepatic triglyceride content and lipid droplets in liver tissues, as well as serum levels of liver enzymes, were markedly decreased in db/db mice. DLK1 treatment induced phosphorylation of AMPK and ACC and suppressed nuclear expression of SREBP-1c in the mouse liver or hepatocytes, indicating regulation of fatty acid oxidation and synthesis pathways. Furthermore, DLK1-treated mice showed significantly lower levels of fasting and random glucose, with improved glucose and insulin tolerance compared with the vehicle-treated group. Macrophage infiltration and proinflammatory cytokine levels in the epididymal fat were decreased in DLK1-treated db/db mice. Moreover, DLK1 suppressed glucose production from hepatocytes, which was blocked after co-administration of an AMPK inhibitor, compound C. DLK1-treated hepatocytes and mouse liver tissues showed lower PEPCK and G6Pase expression. DLK1 triggered AKT phosphorylation followed by cytosolic translocation of FOXO1 from the nucleus in hepatocytes.

Conclusions:

The present study demonstrated that exogenous administration of DLK1 reduced hepatic steatosis and hyperglycemia via AMPK activation in the liver. This result suggests that DLK1 may be a novel therapeutic approach for treating NAFLD and diabetes.

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Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2012R1A1A2043812). The authors would like to thank Dong-Su Jang, MFA, (Medical Illustrator, Medical Research Support Section, Yonsei University College of Medicine, Seoul, Korea) for his help with the illustrations.

Author contributions

Y.-h.L., and B.-S.C. designed research; Y.L., M.R.Y., H.M.K., B.H.J. and B.-C.P. performed research; B.-C.P. and Y.W.P. contributed materials/analytic tools; Y.-h.L., M.R.Y., B.-W.L. and E.S.K. analyzed data; B.-W.L., E.S.K. and H.C.L. provided critical revision of the article for important intellectual content; and Y.L., H.C.L. and B.-S.C. wrote the paper.

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Author notes

  1. Y-h Lee and M R Yun: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

    Y-h Lee, M R Yun, B H Jeon, B-W Lee, E S Kang, H C Lee & B-S Cha

  2. Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea

    H M Kim

  3. Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

    B-C Park & Y W Park

  4. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea

    B-S Cha

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  1. Y-h Lee
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Lee, Yh., Yun, M., Kim, H. et al. Exogenous administration of DLK1 ameliorates hepatic steatosis and regulates gluconeogenesis via activation of AMPK. Int J Obes 40, 356–365 (2016). https://doi.org/10.1038/ijo.2015.173

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