Tryptophan and polyamine metabolism dysregulation serves as an early marker of high-fat diet-induced glucose intolerance

A high-fat diet (HFD) induces metabolic dysfunction early, before the onset of the classic obese phenotype. However, understanding this early process remains limited, and potential diagnostic systems are still poorly investigated, particularly in childhood obesity. Continuous blood glucose monitoring was performed in mice to evaluate the early metabolic effects of HFD exposure. Metabolomic and transcriptomic analyses were conducted to characterize metabolic and transcriptional changes at various HFD feeding stages and investigate underlying mechanisms. Venn analysis was applied to identify metabolites specific to early HFD exposure. These metabolites were further compared with those detected in obese children to identify potential early warning biomarkers of obesity. Week 3 of HFD feeding was identified as a critical turning point in metabolic dysfunction in mice. Metabolomic profiling revealed that significant metabolic remodeling had occurred before glucose intolerance, particularly involving alterations in tryptophan metabolism, polyamine metabolism, and glycerophospholipid metabolism. Moreover, 54 HFD-specific metabolites were identified during this early stage. Further analysis identified serotonin, formiminoglutamate, inosine, and spermine as potential early warning biomarkers for HFD-induced obesity. Finally, transcriptomic profiling revealed early activation of interleukin-17A and type I interferon pathways, implicating immune involvement in metabolic perturbations. Early HFD exposure induces metabolic reprogramming before the onset of glucose intolerance. These_under_edi findings provide new insights into the mechanisms of diet-induced metabolic dysfunction and support the identification of potential biomarkers for early detection, particularly in childhood obesity. Early high-fat diet exposure induces metabolic reprogramming before glucose intolerance, characterized by alterations in tryptophan and polyamine metabolism and revealing candidate early biomarkers of obesity.