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.
Highlights
Adipocytes develop through a chain of events starting with the proliferation of mesenchymal stem cells (MSC) which subsequently differentiate into pre-adipocytes and into mature adipocytes [1]
Comparison of organ weights in Tartrate resistant acid phosphatase (TRAP)+ versus nontransgenic littermate weight–growth curves Male (WT) mice showed that two groups of organs were increased in TRAP+ mice; (1) lymphoid organs i.e. spleen by,50% and (2) different adipose tissue depots i.e. mesenteric- and brown fat by,60–120% depending on depot (Figure 1B and Table S2)
The weights of other major internal organs e.g. liver, heart and kidneys, relative to total body mass were reduced in TRAP+ compared to WT mice
Summary
Adipocytes develop through a chain of events starting with the proliferation of mesenchymal stem cells (MSC) which subsequently differentiate into pre-adipocytes and into mature adipocytes [1]. Human adipose tissue-derived MSCs can develop into multiple lineages including adipocytes, osteoblasts, chondrocytes and myocytes [5]. One possible regulator of osteoblast differentiation and bone formation is the osteoclast-/ macrophage-derived metalloenzyme tartrate-resistant acid phosphatase (TRAP) [9,10]. Obesity is associated with macrophage infiltration of adipose tissue, which may link adipose inflammation to insulin resistance. 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
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