High-intensity interval training identifies lipocalin 2 as a potential therapeutic target for hypothalamic neuroprotection in obesity

INTRODUCTION: Obesity is characterized by hypothalamic dysfunction and metabolic dysregulation. While high-intensity interval training (HIIT) effectively treats obesity, the underlying central mechanisms remain unclear. This study aims to investigate HIIT's effects onmetabolic parameters and hypothalamic gene expression, exploring possible pathways linking central and peripheral adaptations. MATERIAL AND METHODS: Our study evaluated HIIT-induced metabolic changes in male diet-induced obese (DIO) mice. Body weightand caloric intake were recorded throughout the intervention period, and glucose regulation was assessed via glucose tolerance test(GTT) and insulin tolerance test (ITT). Following the HIIT intervention, blood was collected for cytokine assessment and hypothalamictissue was harvested for molecular characterization. RNA sequencing (RNA-seq) was employed to analyze gene expression, with enrichmentanalysis to identify biological pathways, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) to validate keyfindings. Protein expression was examined through Western blotting, and circulating cytokine levels were quantified using enzyme-linkedimmunosorbent assay (ELISA). RESULTS: High-intensity interval training significantly reduced caloric intake while improving glucose metabolism and insulin sensitivity in DIO mice, accompanied by hypothalamic transcriptomic remodeling. RNA-seq identified 178 upregulated and 292 downregulated genes post-HIIT,with pathway enrichment analysis revealing activation of interleukin 17 (IL-17) signaling. Notably, HIIT increased hypothalamic lipocalin 2(Lcn2) mRNA and protein expression, which correlated with decreased hypothalamic apoptosis and elevated hypothalamic pro-opiomelanocortin(POMC) expression in DIO mice. Consistently, circulating IL-17 levels were elevated following HIIT intervention. CONCLUSIONS: Collectively, our findings identify hypothalamic Lcn2 as a prominent molecular responder to short-term HIIT training, whoseupregulation parallels enhanced IL-17 signaling and coincides with the recovery of POMC neurons.