Monomeric Tartrate Resistant Acid Phosphatase Induces Insulin Sensitive Obesity

Abstract

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.

Expression and secretion of the novel adipokine tartrate-resistant acid phosphatase from adipose tissues of obese and lean women

“…Moreover, TRAP is overexpressed in the adipose tissue of obese humans. 10 The cellular origin of TRAP in the adipose tissue is not fully settled, although total TRAP and TRAP 5a co-localized with the monocyte/macrophage marker CD68. 10 However, as CD68 is also expressed by other cell types besides macrophages, 32 we determined the expression pattern of TRAP in different cells of the human adipose tissue.…”

“…10 The cellular origin of TRAP in the adipose tissue is not fully settled, although total TRAP and TRAP 5a co-localized with the monocyte/macrophage marker CD68. 10 However, as CD68 is also expressed by other cell types besides macrophages, 32 we determined the expression pattern of TRAP in different cells of the human adipose tissue. Separation of different cell types by immunodepletion/selection, followed by TRAP mRNA quantification revealed that TRAP is highly expressed per cell in ATMs compared with mature adipocytes, adipocyte progenitor cells, endothelial cells and cells negative for CD34, CD14 and CD31 in both lean and obese subjects.…”

“…[7][8][9] Recently, we showed that TRAP 5a, but not TRAP 5b, induces obesity in mice and is increased in the adipose tissue of obese humans. 10 Furthermore, TRAP 5a, but not TRAP 5b, induces both proliferation and differentiation of mouse and human adipocyte precursors in vitro. This suggests that TRAP 5a is important for adipogenesis, and that the major source in the adipose tissue seems to be adipose tissue macrophages (ATMs).…”

“…23,24 So far, only two studies have investigated the expression and function of TRAP in the adipose tissue. 10,11 A number of clinically relevant issues are still unsolved such as: whether TRAP is expressed in adipose tissue cells other than ATMs; which isoforms of TRAP are secreted from the adipose tissue and whether the secretion of TRAP is correlated with that of other known cytokines/adipokines from the adipose tissue? This study was designed to answer these questions by investigating human subcutaneous adipose tissues derived from lean and obese women.…”

Macrophage gene expression is related to obesity and the metabolic syndrome in human subcutaneous fat as well as in visceral fat

“…Other genes of the list, such as HLA-DR, M130, CDSIGN and IL-10 (also known as IL10), have been shown to be highly expressed in human ATMs [22,23]. TRAP is highly expressed in adipose tissue of obese individuals where it is secreted from ATM [42]. Second, we investigated the association between ATMspecific gene expression levels and clinical variables in paired SAT and VAT samples from four thoroughly phenotyped groups of lean, overweight, obese and the metabolic syndrome individuals.…”