Sex-Dependent Lipidomic Remodeling in Plasma and Feces Following High-Fat Diet Intake in Adult Rats

Background/Objectives: This study aimed to characterize the effects of high-fat-diet (HFD)-induced metabolic stress on both plasma and fecal lipidomes in rats, and to determine the influence of sex on these responses. Methods: Adult female and male Wistar rats were fed either a standard diet (REF) or HFD (45% lard fat diet) for 12 weeks and metadata were collected over time. Plasma and feces samples were collected and subjected to semi-targeted lipidomic profiling by mass spectrometry. Results: HFD induced significant morphometric and metabolic alterations in both sexes, with a more pronounced metabolic phenotype in males. Plasma lipidomics revealed extensive diet-driven induced remodeling across multiple lipid classes, driven primarily by changes in individual lipid species level rather than total class abundance. Although sex significantly influenced the plasma lipidome in both dietary conditions, the direction of HFD-induced changes in individual lipid species was largely concordant between females and males. In contrast, the fecal lipidome showed limited global remodeling but displayed distinct changes in specific lipid subclasses. Notably, fecal long-chain acylcarnitines (ACar) were consistently increased in HFD animals of both sexes. Fecal ACar 16:0 and ACar 18:1 were positively associated with body weight gain in the HFD group, whereas no significant associations were detected in REF animals. Conclusions: These findings reveal distinct systemic and intestinal lipidomic responses to HFD and highlight the value of integrating fecal lipidomics alongside plasma profiling while considering sex as a fundamental biological variable in metabolic research.