N-Lactoyl-Phenylalanine modulates lipid metabolism in microglia/macrophage via the AMPK-PGC1α-PPARγ pathway to promote recovery in mice with spinal cord injury.

Abstract

The accumulation of lipids in microglia/macrophage-induced inflammation exacerbation represents a pivotal factor contributing to secondary injury following spinal cord injury (SCI). N-Lactoyl-Phenylalanine (L-P), a metabolic byproduct of exercise, exhibits the capacity to regulate carbohydrate and lipid metabolism and may serve as a potential regulator of lipid metabolism in microglia/macrophage. This study investigates the role of L-P in modulating lipid homeostasis in microglia/macrophage and its therapeutic implications for SCI recovery. By establishing a mouse model of SCI, we confirmed that L-P administration markedly altered lipid metabolism in microglia/macrophage. This metabolic reprogramming was mediated through the activation of the AMPK-PGC1α-PPARγ signaling pathway, which plays a crucial role in regulating cellular energy metabolism and inflammatory responses. Our findings demonstrate that L-P treatment enhances the lipid metabolic capacity of microglia/macrophage, thereby attenuating neuroinflammation and promoting tissue repair after injury. Moreover, the polarization of microglia/macrophage shifts toward the anti-inflammatory M2 phenotype, providing substantial support for the regenerative process of the injured spinal cord. Functional analysis revealed that mice treated with L-P exhibited significantly improved motor function compared to the control group. Collectively, these results underscore the therapeutic potential of L-P in SCI and suggest its utility as a metabolic intervention strategy by modulating microglia/macrophage lipid metabolism to accelerate recovery.