Background & Aim
Macrophages are key modulators of hepatic development and systemic metabolic homeostasis. Our previous studies demonstrate that acute administration of a macrophage colony‑stimulating factor (CSF1)–Fc fusion protein reprograms metabolism—reducing adiposity, increasing lean mass, and lowering glycaemia independently of caloric intake—while promoting hepatocyte proliferation, liver growth, and repair in injury and fibrosis. We hypothesised that CSF1‑driven macrophage activation confers therapeutic benefit in diabetes‑associated metabolic dysfunction, including metabolic dysfunction‑associated steatotic liver disease (MASLD).
Methods
We evaluated acute CSF1 (four daily injections) across four complementary models encompassing distinct features of metabolic disease and MASLD: western diet–induced steatosis, Alms1−/− mice, diabetic Leprdb-/- mice, and a choline‑deficient amino acid–defined (CDAA) diet model of fibrosis. Changes in body composition, liver size, liver fat, glucose regulation, fibrosis, and circulating insulin and proinsulin were assessed.
Results
CSF1 rapidly increased macrophage numbers in metabolic tissues, driven by enhanced growth of resident macrophages and recruitment of monocyte derived macrophages. Across all models, CSF1 consistently reduced fat mass, increased lean mass and liver mass, reflecting strong regenerative activity. Liver fat content reduced significantly, indicating an improvement in steatosis. In diabetic mice, CSF1 produced clear metabolic benefits including reduced blood glucose and circulating insulin and proinsulin, suggesting improved metabolic efficiency. In the fibrosis model, CSF1 reduced collagen accumulation, indicating an anti‑fibrotic effect. At gene‑expression level, the response was associated with increased Timd4 in models without advanced fibrosis, while Trem2 was consistently upregulated across all models, pointing to activation of a lipid‑responsive, tissue‑repair macrophage state.
Discussion/Conclusion
Acute CSF1 administration reprograms liver macrophages toward regenerative, anti‑fibrotic, and metabolically favorable phenotypes, improving glycaemic control and reducing insulin/proinsulin burden alongside resolution of steatosis and fibrosis. These data support CSF1‑based strategies as a promising therapeutic avenue for diabetes‑associated MASLD, either as monotherapy or in rational combination with current metabolic agents.