High-Intensity Interval Training Improves Memory Deficits in Obese Mice by Enhancing Osteocalcin-Driven Astrocytic BDNF Expression and Stimulating Hippocampal Neurogenesis

Obesity contributes to cognitive disorders, particularly memory impairment. Physical exercise is a non-pharmacological approach for enhancing weight management and promoting brain health. Especially, high-intensity interval training (HIIT) yields results comparable to or even exceeding those of traditional aerobic exercises. However, its nootropic effects and underlying mechanisms remain unclear. This study aims to investigate the cognitive-enhancing effects of high-intensity interval training (HIIT) in the context of neurotoxicity induced by a high-calorie diet, with particular emphasis on the role of osteocalcin (OCN)/GPR158 signaling in adult hippocampal neurogenesis. Mice were fed a high-fat, high-sucrose diet (HFHSD) for 12 weeks. They then participated in an 8-week HIIT program, with the training intensity determined based on their pre-assessed maximal running capacity (MRC). HIIT efficiently regulated body weight and feeding behavior while improving MRC. It also ameliorated HFHSD-induced memory deficits, as demonstrated by the modified Y-maze test, by promoting adult hippocampal neurogenesis, which was primarily localized to the dorsal hippocampus. Moreover, HIIT markedly increased astrocytic OCN/GPR158 signaling and significantly elevated BDNF expression in astrocytes within the dentate gyrus. Activation of the AKT/GSK3β pathway was also detected in OCN-positive astrocytes. This study collectively suggests a HIIT-specific mechanism, indicating that astrocytic OCN/GPR158 may contribute significantly to memory improvement in HFHSD-fed mice through its proneurogenic effects. Therefore, HIIT could serve as an effective strategy for combating the cognitive decline associated with metabolic disorders.