LECT2 Functions as a Hepatokine That Links Obesity to Skeletal Muscle Insulin Resistance
- Fei Lan1,
- Hirofumi Misu1,
- Keita Chikamoto1,2,
- Hiroaki Takayama1,
- Akihiro Kikuchi1,
- Kensuke Mohri1,
- Noboru Takata1,
- Hiroto Hayashi1,
- Naoto Matsuzawa-Nagata1,
- Yumie Takeshita1,
- Hiroyo Noda1,
- Yukako Matsumoto1,
- Tsuguhito Ota1,
- Toru Nagano3,
- Masatoshi Nakagen3,
- Ken-ichi Miyamoto4,5,
- Kanako Takatsuki6,
- Toru Seo6,
- Kaito Iwayama7,
- Kunpei Tokuyama7,
- Seiichi Matsugo8,9,
- Hong Tang10,
- Yoshiro Saito11,
- Satoshi Yamagoe12,
- Shuichi Kaneko1 and
- Toshinari Takamura1⇑
- 1Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
- 2Division of Natural System, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa, Japan
- 3Public Central Hospital of Matto Ishikawa, Hakusan, Ishikawa, Japan
- 4Department of Hospital Pharmacy, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
- 5Department of Medicinal Informatics, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
- 6Merck & Co. Inc., Rahway, NJ
- 7Division of Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan
- 8Division of Material Engineering, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan
- 9Institute of Science and Engineering, Faculty of Natural System, Kanazawa University, Kanazawa, Japan
- 10Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- 11Department of Medical Life Systems, Faculty of Medical and Life Sciences, Doshisha University, Kyotanabe, Kyoto, Japan
- 12Department of Bioactive Molecules, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan
- Corresponding author: Toshinari Takamura, .
F.L. and H.M. contributed equally to this study.
Recent articles 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 called hepatokines. Here we demonstrate that leukocyte cell–derived chemotaxin 2 (LECT2), 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 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 Jun NH2-terminal kinase 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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0728/-/DC1.
- Received May 6, 2013.
- Accepted January 14, 2014.
- © 2014 by the American Diabetes Association.
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