Pathological roles of bone marrow adipocyte-derived monocyte chemotactic protein-1 in type 2 diabetic mice

Abstract Type 2 diabetes mellitus (T2DM) has become a prevalent public health concern, with beta-cell dysfunction involved in its pathogenesis. Bone marrow adipose tissue (BMAT) increases in both the quantity and area in individuals with T2DM along with heightened monocyte chemotactic protein-1 (MCP-1) secretion. This study aims to investigate the influence and underlying mechanisms of MCP-1 originating from bone marrow adipocytes (BMAs) on systemic glucose homeostasis in T2DM. Initially, a substantial decrease in the proliferation and glucose-stimulated insulin secretion (GSIS) of islet cells was observed. Moreover, a comparative analysis between the control (Ctrl) group and db/db mice revealed significant alterations in the gene expression profiles of whole bone marrow cells, with a noteworthy upregulation of Mcp-1. And the primary enriched pathways included chemokine signaling pathway and AGE-RAGE signaling pathway in diabetic complications. In addition, the level of MCP-1 was distinctly elevated in BMA-derived conditional media (CM), leading to a substantial inhibition of proliferation, GSIS and the protein level of phosphorylated Akt (p-Akt) in Min6 cells. After blocking MCP-1 pathway, we observed a restoration of p-Akt and the proliferation of islet cells, resulting in a marked improvement in disordered glucose homeostasis. In summary, there is an accumulation of BMAs in T2DM, which secrete excessive MCP-1, exacerbating the abnormal accumulation of BMAs in the bone marrow cavity through paracrine signaling. The upregulated MCP-1, in turn, worsens glucose metabolism disorder by inhibiting the proliferation and insulin secretion of islet cells through an endocrine pathway. Inhibiting MCP-1 signaling can partially restore the proliferation and insulin secretion of islet cells, ultimately ameliorating glucose metabolism disorder. It’s worth noting that to delve deeper into the impact of MCP-1 derived from BMAs on islet cells and its potential mechanisms, it is imperative to develop genetically engineered mice with conditional Mcp-1 knockout from BMAs.