Monomeric Tartrate Resistant Acid Phosphatase Induces Insulin Sensitive Obesity

BackgroundObesity is associated with macrophage infiltration of adipose tissue, which may link adipose inflammation to insulin resistance. However, the impact of inflammatory cells in the pathophysiology of obesity remains unclear. Tartrate resistant acid phosphatase (TRAP) is an enzyme expressed by subsets of macrophages and osteoclasts that exists either as an enzymatically inactive monomer or as an active, proteolytically processed dimer.
Principal FindingsUsing mice over expressing TRAP, we show that over-expression of monomeric, but not the dimeric form in adipose tissue leads to early onset spontaneous hyperplastic obesity i.e. many small fat cells. In vitro, recombinant monomeric, but not proteolytically processed TRAP induced proliferation and differentiation of mouse and human adipocyte precursor cells. In humans, monomeric TRAP was highly expressed in the adipose tissue of obese individuals. In both the mouse model and in the obese humans the source of TRAP in adipose tissue was macrophages. In addition, the obese TRAP over expressing mice exhibited signs of a low-grade inflammatory reaction in adipose tissue without evidence of abnormal adipocyte lipolysis, lipogenesis or insulin sensitivity.
ConclusionMonomeric TRAP, most likely secreted from adipose tissue macrophages, induces hyperplastic obesity with normal adipocyte lipid metabolism and insulin sensitivity.

研究背景
肥胖与脂肪组织巨噬细胞浸润密切相关，该过程可能将脂肪组织炎症与胰岛素抵抗联系起来。然而，炎症细胞在肥胖病理生理学中的作用仍不明确。酒石酸抗性酸性磷酸酶（Tartrate resistant acid phosphatase, TRAP）是一类由巨噬细胞亚群与破骨细胞表达的酶，该酶以无酶活性的单体形式，或经蛋白水解加工后的活性二聚体形式存在。

主要研究结果
本研究利用过表达TRAP的小鼠模型发现，在脂肪组织中过表达单体型TRAP（而非二聚体形式）可诱发早发性自发性增生性肥胖，即形成大量小型脂肪细胞。体外实验表明，重组单体型TRAP（而非经蛋白水解加工后的TRAP）可诱导小鼠及人脂肪细胞前体细胞的增殖与分化。在人体中，单体型TRAP在肥胖个体的脂肪组织中呈高表达状态。无论是在小鼠模型还是肥胖人群中，脂肪组织中TRAP的来源均为巨噬细胞。此外，过表达TRAP的肥胖小鼠在脂肪组织中出现低度炎症反应，但未观察到脂肪细胞脂解、脂肪生成或胰岛素敏感性异常的现象。

研究结论
单体型TRAP极有可能由脂肪组织巨噬细胞分泌，可诱导增生性肥胖，且脂肪细胞脂质代谢与胰岛素敏感性维持正常。