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
Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan Computational Diagnostic Radiology and Preventive Medicine, University of Tokyo, Tokyo, Japan.
Diabetes. 2014 Dec;63(12):4154-64. doi: 10.2337/db13-1694. Epub 2014 Jun 26.
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.
体重受食物摄入和能量消耗的严格调节，肥胖与能量消耗减少有关。在此，我们发现核苷酸焦磷酸酶/磷酸二酯酶 2（ENPP2，自分泌酶）是一种脂肪来源的分泌性酶，可控制脂肪扩张、棕色脂肪组织（BAT）功能和能量消耗。在小鼠中，Enpp2 在内脏白色脂肪组织和 BAT 中高表达，在肥大的脂肪细胞/脂肪组织中表达下调。高脂饮食喂养的 Enpp2(+/-) 小鼠和脂肪细胞特异性 Enpp2 敲除小鼠比喂养相同饮食的对照小鼠体重增加更少，胰岛素抵抗也更小。BAT 的功能更活跃，能量消耗增加。在人类中，肥胖受试者的皮下脂肪中 ENPP2 的表达和血清中的 ENPP2 水平降低。综上所述，我们的研究结果确立了 ENPP2 是一种脂肪来源的分泌性酶，可调节脂肪肥胖和全身代谢。它们还表明，ENPP2 可能是治疗代谢性疾病的有用治疗靶点。
