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

Abstract

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.

Keywords: Obesity; Pancreas; Macrophages; Metabolic dysfunction; Inflammation response

Core Tip: Obesity contributes to the polarisation of pancreatic macrophages towards pro-inflammatory Macrophage, pro-inflammatory phenotype type through chronic inflammation, releasing factors such as C-C motif ligand 2 and transforming growth factor beta that impair β-cell function and trigger fibrosis. Macrophage metabolites and their interactions with vesicular cells have been identified as key mechanisms of metabolic disorders. Targeted regulation of macrophage polarisation such as the PPAR-γ pathway shows therapeutic potential. Future studies need to focus on macrophage subpopulation heterogeneity to develop precise therapeutic strategies.