Impaired Macrophage-Mediated Collagen Uptake Characterizes Insulin Resistance-Associated Adipose Tissue Fibrosis

Researchers from the University of Gothenburg have identified a mechanism involving impaired macrophage function in adipose tissue that may help explain why some individuals with obesity develop type 2 diabetes while others do not. The study, published in PNAS, highlights the importance of efficient collagen removal during adaptive subcutaneous adipose tissue (SAT) expansion, a process that protects against ectopic lipid deposition during weight gain. The research indicates that the impaired function of macrophages in handling collagen breakdown may contribute to the development of insulin resistance and type 2 diabetes in individuals with obesity. The study suggests that collagen-degrading macrophages and collagen fragments could be potential therapeutic targets for preventing type 2 diabetes and other conditions associated with impaired tissue remodeling.

Key Points:

1. Adipose Tissue Expansion and Collagen Breakdown: Efficient removal of fibrillar collagen is crucial for adaptive subcutaneous adipose tissue (SAT) expansion, protecting against ectopic lipid deposition during weight gain.
2. Macrophage-Mediated Collagen Uptake: The breakdown of collagen in expanding SAT involves the engagement of resident M2-like macrophages in collagen endocytosis. These macrophages display increased CD206-mediated involvement in collagen endocytosis during weight gain.
3. Role of CD206: The study shows that CD206-mediated engagement in collagen endocytosis by M2-like macrophages is associated with the proliferation of these macrophages in expanding SAT.
4. Blockage of CD206: Blocking CD206 during acute high-fat diet-induced weight gain leads to SAT collagen fragment accumulation, accompanied by elevated inflammation and fibrosis markers.
5. Diminished Macrophage Function in Obesity: In obesity, macrophages in SAT experience diminished engagement in collagen endocytosis, leading to elevated levels of collagen fragments.
6. Biological Actions of Collagen Fragments: Collagen fragments in SAT, resulting from impaired macrophage function, exert biological actions. They stimulate macrophage proliferation and cause fibroinflammatory effects in fibroblasts.
7. Implications for Therapeutic Targets: The study suggests that the macrophage-collagen fragment axis in physiological SAT expansion is disrupted in obesity, leading to pathological adipose tissue remodeling. Targeting this process therapeutically may offer a means to prevent obesity-related metabolic disorders, including type 2 diabetes.
8. Human Relevance: While the study is mainly based on experiments in mice, the research suggests that the newly discovered mechanism involving macrophage-collagen fragment interactions also applies to humans.
9. Potential for Biomarkers: Certain collagen fragments could serve as measurable biological markers, identifying individuals at a higher risk of developing type 2 diabetes.

Conclusion:

The University of Gothenburg study identifies impaired macrophage-mediated collagen uptake in adipose tissue as a potential mechanism contributing to insulin resistance and type 2 diabetes in individuals with obesity. The impaired function of macrophages in handling collagen breakdown during weight gain may lead to the accumulation of collagen fragments in adipose tissue, influencing various cellular processes such as inflammation and cell division. The study suggests that therapeutic targeting of the macrophage-collagen fragment axis could be a means to prevent pathological adipose tissue remodeling and reduce the risk of obesity-related metabolic disorders, including type 2 diabetes. The findings also point to the potential of certain collagen fragments as measurable biological markers for identifying individuals at higher risk of developing type 2 diabetes.

More information: Milica Vujičić et al, A macrophage-collagen fragment axis mediates subcutaneous adipose tissue remodeling in mice, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2313185121