Journal
DIABETES
Volume 63, Issue 12, Pages 4154-4164Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db13-1694
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Funding
- Japan Society for the Promotion of Science
- Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program)
- Translational Systems Biology and Medicine Initiative from the Ministry of Education, Culture, Sports, Science and Technology of Japan
- Global Centers of Excellence Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan
- National Institute of Biomedical Innovation
- Grants-in-Aid for Scientific Research [25253040, 22116004] Funding Source: KAKEN
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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.
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