The Zucker (fa/fa) rat is a valuable and extensively utilized model for obesity research. However, the metabolic
networks underlying the systemic response in the obese Zucker rats remain to be elucidated. This information is important
to further our understanding of the circulation of the microbial or host-microbial metabolites and their impact on host
metabolism. 1H Nuclear Magnetic Resonance spectroscopy-based metabolic profiling was used to probe global metabolic
differences in portal vein and peripheral blood plasma, urine and fecal water between obese (fa/fa, n=12) and lean (fa/+,
n=12) Zucker rats. Urinary concentrations of host-microbial co-metabolites were found to be significantly higher in lean
Zucker rats. Higher concentrations of fecal lactate, short chain fatty acids (SCFAs), 3-hydroxyphenyl propionic acid and
glycerol, and lower levels of valine and glycine were observed in obese rats compared with lean animals. Regardless of
phenotype, concentrations of SCFAs, tricarboxylic acid cycle intermediates, and choline metabolites were higher in portal
vein blood compared to peripheral blood. However, higher levels of succinate, phenylalanine and tyrosine were observed
in portal vein blood compared with peripheral blood from lean rats but not in obese rats. Our findings indicate that the
absorption of propionate and acetate, choline and TMA are independent of the Zucker rat phenotypes. However, urinary
host-microbial co-metabolites were highly associated with phenotypes, suggesting distinct gut microbial metabolic activities
in lean and obese Zucker rats. This work advances our understanding of metabolic processes associated with obesity,
particularly the metabolic functionality of the gut microbiota in the context of obesity.