ENPP2 contributes to adipose tissue expansion in diet-induced obesity
- Satoshi Nishimura1,2,6,
- Mika Nagasaki1,3,
- Shinichi Okudaira7,
- Junken Aoki7,
- Tsukasa Ohmori6,
- Ryunosuke Ohkawa4,
- Kazuhiro Nakamura4,
- Koji Igarashi8,
- Hiroshi Yamashita1,
- Koji Eto9,
- Kansei Uno1,3,
- Naoto Hayashi3,
- Takashi Kadowaki2,5,
- Issei Komuro1,
- Yutaka Yatomi4 and
- Ryozo Nagai6
- 1Department of Cardiovascular Medicine,
- 2Translational Systems Biology and Medicine Initiative,
- 3Computational Diagnostic Radiology and Preventive Medicine,
- 4Department of Clinical Laboratory,
- 5Department of Metabolic Diseases, The University of Tokyo, Japan;
- 6Reserach Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan,
- 7Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miygai, Japan;
- 8Bioscience Division, Reagent Development Department, AIA Research Group, TOSOH Corporation, Kanagawa, Japan and
- 9Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan,
- Corresponding Author: S. Nishimura Satoshi Nishimura, E-mail:
Body weight is tightly regulated by food intake and energy dissipation, and obesity is related to decreased energy expenditure (EE). Herein, we show that nucleotide pyrophosphatase/phosphodieseterase 2 (ENPP2, autotaxin) is an adipose-derived, secreted enzyme that controls adipose expansion, brown adipose tissue (BAT) function, and EE. In mice, Enpp2 was highly expressed in visceral white adipose tissue and BAT, and is downregulated in hypertrophied adipocytes/adipose tissue. Enpp2+/- mice and adipocyte-specific Enpp2 knockout mice fed a high-fat diet showed smaller body weight gains and less insulin resistance than control mice fed the same diet. BAT was functionally more active, and EE was increased in Enpp2-deficient mice. In humans, ENPP2 expression in subcutaneous fat and ENPP2 levels in serum were reduced in obese subjects. Taken together, our results establish ENPP2 as an adipose-derived, secreted enzyme that regulates adipose obesity and systemic metabolism. They also suggest ENPP2 could be a useful therapeutic target for the treatment of metabolic disease.
- Received November 5, 2013.
- Accepted June 22, 2014.
- © 2014 by the American Diabetes Association.
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