Altered expression of leptin and leptin receptor in the development of immune‑mediated aplastic anemia in mice

Abstract

The current study aimed to explore the levels of leptin (LEP) and LEP receptor (LEP-R) on the progression of aplastic anemia (AA) with bone marrow fat conversion. An AA model was developed by infusing C57BL/6 lymph node cells into BALB/c mice. At 0, 3, 6, 9, 12, 15 and 18 days after modeling, routine blood counts, bone marrow biopsy slides, lymphocyte subsets (CD4 + and CD8 + T cells) and cytokine levels [including interleukin (IL)-2, IL-4, IL-5 and interferon-γ] were assessed. LEP and LEP-R levels in peripheral blood serum, mesenchymal stem cells (MSCs) and bone marrow were also analyzed by enzyme-linked immunosorbent assay, polymerase chain reaction and immunohistochemistry. The relevance of LEP, LEP-R and other factors was analyzed by Pearson's correlation analysis. Peripheral pancytopenia (reduced count of white blood cells, red blood cells, hemoglobin and platelets), abnormal immune factor levels and histological changes in bone marrow sections were detected in the AA model mice, suggesting that these mice mimicked the pathological changes commonly observed in AA. In addition, following the establishment of AA, the LEP level was gradually increased and the LEP-R level was reduced in the mice over time (P<0.05). The expression of adipogenic genes, including CCAAT/enhancer-binding protein (C/EBP)α, C/EBPβ and peroxisome proliferator-activated receptor γ, was markedly increased, while the expression of the osteogenic gene runt-related transcription factor 2 was reduced compared with the levels in the control group (P<0.05). Taken together, damage to LEP-R may lead to dysregulation of LEP and the enhancement of MSCs to differentiate into adipocytes, resulting in excessive fat in bone marrow of AA patients.

Expression of LEP, LEPR and PGC1A genes is altered in peripheral blood mononuclear cells of patients with relapsing-remitting multiple sclerosis

“…Hence, considering our results, further research on potential gender-specific LEPR signaling in MS is suggested. Recently, LEPR downregulation has been demonstrated in mesenchymal stem cells of mice with the immune-mediated disease (Yin et al, 2019). We may assume that a decrease in LEPR would result in the mitigating effects of LEP, which might be protective in MS and is supported by currently identified significant positive correlation of LEPR mRNA levels with both EDSS and MSSS.…”

Bone Marrow Adipose Tissue

“…Additionally, in an AA mouse model, it has been shown that leptin levels increased both in the plasma and in bone marrow. Moreover, the increase in leptin is positively correlated with T cell function disorder and inversely correlated with bone marrow hematopoietic capacity [103]. It is well known that leptin is implicated in inflammation of the bone marrow microenvironment, in immune regulation, and in hematopoiesis.…”

Marrow Fat-Secreted Factors as Biomarkers for Osteoporosis

“…Reducing marrow adiposity in rats by sympathetic nervous blockade results in a substantial reduction of serum leptin concentration [70••]. Conversely, the expansion of MAT in mice after the induction of aplastic anemia leads to a marked increase of peripheral serum leptin by approximately 50% [71]. It remains to be clarified if local leptin production influences bone metabolism beyond that of leptin production outside the bone marrow cavities.…”