12-Lipoxygenase Inhibition Improves Glycemia and Obesity-associated Inflammation in Male Human Gene Replacement Mice.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Obesity-associated inflammation is characterized by macrophage infiltration into peripheral tissues, contributing to the progression of prediabetes and type 2 diabetes. 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and promotes 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 used 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 male 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 β-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 β-cell dedifferentiation and reduced macrophage infiltr

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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