Macrophage-mediated metabolic dysregulation in the pancreas: Insights from obesity

Obesity is a major contributor to metabolic dysfunction, and its impact on pancreatic health has garnered increasing attention. Macrophages, as key regulators of inflammation and metabolism, play a central role in mediating obesity-induced pancreatic damage. In obese individuals, excessive lipid accumulation and chronic low-grade inflammation drive the infiltration and polarization of macrophages within the pancreas. These macrophages, particularly the pro-inflammatory Macrophage, pro-inflammatory phenotype (M1) phenotype, secrete cytokines such as C-C motif ligand 2 (CCL2) and transforming growth factor beta (TGF-β), which disrupt pancreatic β-cell function and impair insulin secretion. Conversely, anti-inflammatory Macrophage, anti-inflammatory phenotype (M2) macrophages contribute to tissue repair but may also promote fibrotic changes under prolonged metabolic stress. Pancreatic macrophages are activated under high-fat diet conditions, promoting inflammation and impairing β-cell function through the SUCLA2-HIF-1α axis and mechanistic Target of Rapamycin Complex 1 (mTORC1)/PD-1 pathway, thereby establishing a self-perpetuating "metabolic-immunosuppressive" vicious cycle. Targeted intervention strategies against macrophages—such as SUCLA2 inhibitors can ameliorate metabolic dysregulation. Meanwhile, exosome-mediated interorgan communication [e.g. , via microRNA-155 (miR-155) and miR-30a] offers novel insights for multi-system synergistic therapies. Understanding the mechanisms by which macrophages mediate metabolic dysregulation in the pancreas under obese conditions provides critical insights into the pathogenesis of obesity-related pancreatic disorders.