Pathological roles of bone marrow adipocyte-derived monocyte chemotactic protein-1 in aggravating glucose metabolism disorder in type 2 diabetes

Abstract Objective To explore the effect and related mechanisms of bone marrow adipocyte (BMA)-derived monocyte chemotactic protein-1 (Mcp-1) on systemic glucose homeostasis in type 2 diabetes (T2D). Methods Transcriptome sequence, qPCR, ELISA, and immunofluorescence staining were utilized to investigate the alterations in BMA and pancreatic beta-cells. Meanwhile, cell counting kit, flow cytometry, and ELISA were employed to identify cell viability, apoptosis, and glucose-stimulated insulin secretion (GSIS) levels. The protein expression levels were examined using WB. Results Compared with Control (Ctrl) group, the gene expression of whole bone marrow cells from db/db mice showed significant changes, among which Mcp-1 was dramatically up-regulated (Log 2 FC = 2.88), and its major enriched pathway included chemokine signaling pathway and AGE-RAGE signaling pathway in diabetic complications. The BMA was accumulated, the proliferation and GSIS of beta-cells were decreased in T2D mice. The mRNA expression of Mcp-1 in BMA from T2D mice was notably up-regulated. The levels of Mcp-1 in serum and bone marrow supernatant, and the Ccr2 receptor of beta-cells in T2D mice were signally increased. Additionally, the level of Mcp-1 was distinctively elevated in BMA-derived conditional media (CM), which markedly inhibited the proliferation, GSIS and the protein level of p-Akt of the beta-cells. After blocking Mcp-1 pathway in T2D mice, the protein level of p-Akt and the proliferation of beta-cells were restored, the disordered glucose homeostasis was overtly improved as well. Conclusion BMA are accumulated in T2D, which secrete excessive Mcp-1 to aggravate the abnormal accumulation of BMA in bone marrow cavity through paracrine pathway. The up-regulated Mcp-1 can further deteriorate glucose metabolism disorder via restraining the proliferation and insulin secretion of beta-cells by endocrine pathway. Repression of Mcp-1 signaling can partly restore the proliferation and insulin secretion of beta-cells and improve the glucose metabolism disorder.