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bioRxiv · 10.1101/2025.01.10.632274

12-Lipoxygenase inhibition improves glucose homeostasis and obesity-associated inflammation in human gene replacement mice

Kaylan, K. B.·Nargis, T.·Figatner, K.·Wang, J. E.·Pratuangtham, S.·Chakraborty, A.·Casimiro, I.·Nadler, J. L.·Boxer, M. B.·Maloney, D. J.·Anderson, R. M.·Mirmira, R.·Tersey, S. A.
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Abstract

Obesity-associated inflammation is characterized by macrophage infiltration into peripheral tissues, contributing to the progression of prediabetes and type 2 diabetes (T2D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and is known to promote the migration of macrophages, yet its role in obesity-associated inflammation remains incompletely understood. Furthermore, differences between mouse and human orthologs of 12-LOX have limited efforts to study existing pharmacologic inhibitors of 12-LOX. In this study, we utilized a human gene replacement mouse model in which the gene encoding mouse 12-LOX (Alox15) is replaced by the human ALOX12 gene. As a model of obesity and dysglycemia, we administered these mice a high-fat diet. We subsequently investigated the effects of VLX-1005, a potent and selective small molecule inhibitor of human 12-LOX. Oral administration of VLX-1005 resulted in improved glucose homeostasis, decreased {beta} cell dedifferentiation, and reduced macrophage infiltration in islets and adipose tissue. Analysis of the stromal vascular fraction from adipose tissue showed a reduction in myeloid cells and cytokine expression with VLX-1005 treatment, indicating decreased adipose tissue inflammation. In a distinct mouse model in which Alox15 was selectively deleted in myeloid cells, we observed decreased {beta} cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and T2D.

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Kaylan, K. B., Nargis, T., Figatner, K., Wang, J. E., Pratuangtham, S., Chakraborty, A., Casimiro, I., Nadler, J. L., Boxer, M. B., Maloney, D. J., Anderson, R. M., Mirmira, R., Tersey, S. A.. 2025-01-13. 12-Lipoxygenase inhibition improves glucose homeostasis and obesity-associated inflammation in human gene replacement mice. https://doi.org/10.1101/2025.01.10.632274

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