N-Lactoyl-Phenylalanine modulates lipid metabolism in microglia/macrophage via the AMPK-PGC1α-PPARγ pathway to promote recovery in mice with spinal cord injury
Weiyang Ying, Weidong Weng, Peifang Wang, Chi Pan, Jiani Qiu, Qianqian Huang, Gonghao Zhan, Xiaoli Chen
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.