ENPP2 contributes to adipose tissue expansion and insulin resistance in diet-induced obesity

Satoshi Nishimura, Mika Nagasaki, Shinichi Okudaira, Junken Aoki, Tsukasa Ohmori, Ryunosuke Ohkawa, Kazuhiro Nakamura, Koji Igarashi, Hiroshi Yamashita, Koji Eto, Kansei Uno, Naoto Hayashi, Takashi Kadowaki, Issei Komuro, Yutaka Yatomi, Ryozo Nagai

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)4154-4164
Number of pages11
Issue number12
Publication statusPublished - 2014 Dec 1

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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