LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance

  1. Toshinari Takamura1,*
  1. 1Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
  2. 2Division of Natural System, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa, Japan
  3. 3Public Central Hospital of Matto Ishikawa, Hakusan, Ishikawa, Japan
  4. 4Department of Hospital Pharmacy, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
  5. 5Department of Medicinal Informatics, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
  6. 6Merck & Co.Inc.,126E.Lincoln Ave. P.O.Box 2000, Rahway, NJ 07065-0900, USA
  7. 7Division of Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki 305-8575, Japan
  8. 8Division of Material Engineering, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan
  9. 9Institute of Science and Engineering, Faculty of Natural System, Kanazawa University, Kanazawa, Japan
  10. 10Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
  11. 11Department of Medical Life Systems, Faculty of Medical and Life Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
  12. 12Department of Bioactive Molecules, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan
  1. *Corresponding Author: Toshinari Takamura, Email: ttakamura{at}m-kanazawa.jp

Abstract

Recent papers have reported an association between fatty liver disease and systemic insulin resistance in humans, but the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins, termed hepatokines. Here, we demonstrate that leukocyte cell-derived chemotaxin 2 (LECT2), as an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase (AMPK) in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of JNK in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism, and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance.

Footnotes

  • 13 These authors contributed equally to this work.

  • Received May 6, 2013.
  • Accepted January 13, 2014.

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