title: ENPP2 contributes to adipose tissue expansion and insulin resistance in diet-induced obesity.
abstract: 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/phosphodiesterase 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.
authors: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan Translational Systems Biology and Medicine Initiative, University of Tokyo, Tokyo, Japan Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan snishi-tky@umin.ac.jp.
authors: Satoshi
authors: S
authors: Nishimura
authors: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan Computational Diagnostic Radiology and Preventive Medicine, University of Tokyo, Tokyo, Japan.
authors: Mika
authors: M
authors: Nagasaki
authors: Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miygai, Japan.
authors: Shinichi
authors: S
authors: Okudaira
authors: Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miygai, Japan.
authors: Junken
authors: J
authors: Aoki
authors: Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors: Tsukasa
authors: T
authors: Ohmori
authors: Department of Clinical Laboratory, University of Tokyo Hospital, Tokyo, Japan.
authors: Ryunosuke
authors: R
authors: Ohkawa
authors: Department of Clinical Laboratory, University of Tokyo Hospital, Tokyo, Japan.
authors: Kazuhiro
authors: K
authors: Nakamura
authors: Bioscience Division, Reagent Development Department, AIA Research Group, Tosoh Corporation, Kanagawa, Japan.
authors: Koji
authors: K
authors: Igarashi
authors: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
authors: Hiroshi
authors: H
authors: Yamashita
authors: Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Koji
authors: K
authors: Eto
authors: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan Computational Diagnostic Radiology and Preventive Medicine, University of Tokyo, Tokyo, Japan.
authors: Kansei
authors: K
authors: Uno
authors: Computational Diagnostic Radiology and Preventive Medicine, University of Tokyo, Tokyo, Japan.
authors: Naoto
authors: N
authors: Hayashi
authors: Translational Systems Biology and Medicine Initiative, University of Tokyo, Tokyo, Japan Department of Metabolic Diseases, University of Tokyo, Tokyo, Japan.
authors: Takashi
authors: T
authors: Kadowaki
authors: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
authors: Issei
authors: I
authors: Komuro
authors: Department of Clinical Laboratory, University of Tokyo Hospital, Tokyo, Japan.
authors: Yutaka
authors: Y
authors: Yatomi
authors: Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors: Ryozo
authors: R
authors: Nagai
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D015536:Down-Regulation; D004734:Energy Metabolism / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism*; D000099189:Lysophospholipase D
chemical_list: D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D