Mitochondrial biogenesis and fusion are essential for maintaining healthy mitochondria and ATP production. High-intensity interval training (HIIT) can enhance mitochondrial function in mouse hippocampi, but its underlying mechanism is not completely understood. Lactate generated during HIIT may mediate the beneficial effects of HIIT on neuroplasticity by activating the lactate receptor GPR81. Furthermore, growing evidence shows that lactate contributes to mitochondrial function. Given that mitochondrial function is crucial for cerebral physiological processes, the current study aimed to determine the mechanism of HIIT in hippocampal mitochondrial function. In vivo, GPR81 was knocked down in the hippocampi of mice via the injection of adeno-associated virus (AAV) vectors. The GPR81-knockdown mice were subjected to HIIT. The results demonstrated that HIIT increased mitochondria numbers, ATP production, and oxidative phosphorylation (OXPHOS) in the hippocampi of mice. In addition, HIIT induced mitochondrial biogenesis, fusion, synaptic plasticity, and ERK1/2 phosphorylation but not in GPR81-knockdown mice. In vitro, Neuro-2A cells were treated with L-lactate, a GPR81 agonist, and an ERK1/2 inhibitor. The results showed that both L-lactate and the GPR81 agonist increased mitochondrial biogenesis, fusion, ATP levels, OXPHOS, mitochondrial membrane potential, and synaptic plasticity. However, the inhibition of ERK1/2 phosphorylation blunted L-lactate or the GPR81 agonist-induced promotion of mitochondrial function and synaptic plasticity. In conclusion, our findings suggest that lactate mediates HIIT-induced promotion of mitochondrial function through the GPR81-ERK1/2 pathway.

Adiponectin (APN) is a multifunctional adipokine secreted by adipose tissue that has recently been recognized for its important neuroprotective effects in central nervous system (CNS) disorders. However, effective targeted interventions and the precise molecular mechanisms of APN and its receptors remain incompletely understood. Activation of cerebral APN receptor 1 (AdipoR1) through APN supplementation, APN receptor agonists, or exercise interventions can exert beneficial effects in CNS disorders. These effects are mediated through signaling pathways such as AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-alpha (PPARα), leading to enhanced insulin sensitivity, promotion of autophagic clearance of toxic substances, attenuation of neuroinflammation, reduction of oxidative stress and neuronal apoptosis, and improvement of mitochondrial function. This review summarizes the mechanistic associations between APN and various CNS disorders and analyzes the specific intervention strategies, mechanisms, and therapeutic potential of different APN isoforms, APN receptor agonists, and exercise targeting APN receptors. It provides a theoretical basis for exploring effective therapeutic strategies for CNS disorders. In addition, based on the theoretical rationale that both exercise and APN receptor agonists can independently activate the AdipoR1 signaling pathway, future studies may further explore the synergistic effects and potential value of their combined application, thereby providing new research perspectives for promoting brain health.