Adiponectin, a Fat Cell Product, Influences the Earliest Lymphocyte Precursors in Bone Marrow Cultures by Activation of the Cyclooxygenase-Prostaglandin Pathway in Stromal Cells

Abstract

Adiponectin, an adipocyte-derived hormone, is attracting considerable interest as a potential drug for diabetes and obesity. Originally cloned from human s.c. fat, the protein is also found in bone marrow fat cells and has an inhibitory effect on adipocyte differentiation. The aim of the present study is to explore possible influences on lymphohematopoiesis. Recombinant adiponectin strongly inhibited B lymphopoiesis in long-term bone marrow cultures, but only when stromal cells were present and only when cultures were initiated with the earliest category of lymphocyte precursors. Cyclooxygenase inhibitors abrogated the response of early lymphoid progenitors to adiponectin in stromal cell-containing cultures. Furthermore, PGE2, a major product of cyclooxygenase-2 activity, had a direct inhibitory influence on purified hematopoietic cells, suggesting a possible mechanism of adiponectin action in culture. In contrast to lymphopoiesis, myelopoiesis was slightly enhanced in adiponectin-treated bone marrow cultures, and even when cultures were initiated with single lymphomyeloid progenitors. Finally, human B lymphopoiesis was also sensitive to adiponectin in stromal cell cocultures. These results suggest that adiponectin can negatively and selectively influence lymphopoiesis through induction of PG synthesis. They also indicate ways that adipocytes in bone marrow can contribute to regulation of blood cell formation.

Identification of Adiponectin as a Novel Hemopoietic Stem Cell Growth Factor

“…Finally, we identify a potential mechanism of action for adiponectin by demonstrating that inhibition of p38 inhibits adiponectin mediated proliferation. Although previous experiments have demonstrated an inhibitory effect of adiponectin on lymphoid and myeloid-committed cell proliferation (18,35) and experiments in which progenitor KLS cells were cultured with adiponectin resulted in increased myeloid cell production with reduced lymphoid cell growth in vitro (18), the effect of adiponectin stimulation or inhibition on HSCs (51, 52) has not been examined in in vivo transplantation assays. Additionally, previous experiments conducted on the KLS population used the full length recombinant form of adiponectin which only slightly increased proliferation in our experiments when compared to stimulation with the globular domain of adiponectin.…”

“…IL-6 (14 -16) and IL-8 (16), two growth factors derived from adipocytes, have well established roles in the proliferation and differentiation of hemopoietic cells. Prostaglandin, another adipokine, has been demonstrated to have an inhibitory influence on HSCs through induction of apoptosis (17,18). Additionally, leptin has been shown to be required for normal lymphopoiesis (19) by differentially regulating the proliferation of naive and memory T cells (20) and is capable of stimulating the proliferation of myelocytic progenitors (21).…”

“…Furthermore, mice deficient for adiponectin exhibit delayed clearance of free fatty acids from the plasma, severe diet-induced insulin resistance (32), and impaired angiogenic (33) and myocardial (34) repair following ischemic injury. Previous studies have examined the effect of adiponectin on myeloid (35) and lymphoid (18) cells, showing that adiponectin can suppress the growth of these mature cell types in vitro; however, its effects on HSC development are unknown. Here, we sought to investigate the role of adiponectin in hemopoietic stem cells.…”

Adiponectin modulates NK‐cell function

“…Unexpectedly, we detected however, increased NK cells with a lower frequency of effector NK cells and diminished function in APN-deficient mice suggesting a role of APN in NK-cell development. In this regard a modulatory effect of APN on monocyte precursors and B lymphopoiesis has been described in humans [12,13]. Alternatively, as APN −/− mice have a complex phenotype with multiple abnormalities also endothelial trafficking could be different.…”

“…In a recent study we could further demonstrate that T cells store AdipoRs intracellularly, upregulate them upon T-cell receptor activation, and that APN acts as a negative T-cell regulator for antigen-activated T cells [8]. Furthermore, APN has been described as a negative regulator of hematopoiesis inhibiting directly proliferation of myelomonocytic progenitors [12] or indirectly through inducing changes in stromal cells [13]. NK cells are innate effector lymphocytes involved in the first defense against infected or malignant cells.…”