Systemic Characterization of an Obese Phenotype in the Zucker Rat Model Defining Metabolic Axes of Energy Metabolism and Host–Microbial Interactions

Abstract

ABSTRACT: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.1 H 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.

Gut microbiota-derived metabolites in obesity: a systematic review

“…Ahmad et al [29] reported decreased excretion of indoxyl sulfate in obese subjects. An inverse relationship of indoxyl sulfate with BMI has also been shown in other animal and human studies [61,62].…”

Recent Advances in NMR-Based Metabolomics

“…A study using a rat model investigated metabolic profiles of portal vein and peripheral blood plasma, urine, and fecal water of obese and lean animals with a major focus on circulating host-microbial metabolites. 135 This study demonstrated the important association of urinary host-microbial co-metabolites with phenotype. In another study, blood samples collected before and, periodically, after bariatric procedures were investigated to evaluate the metabolic alterations due to bariatric surgery in obese individuals.…”

Boosted TCA cycle enhances survival of zebrafish to Vibrio alginolyticus infection

“…Therefore, it has emerged as a powerful tool to explore metabolic processes, identify crucial metabolic biomarkers and reveal metabolic mechanisms [ 3 ]. Indeed, metabolomics is particularly useful in the study of environment-gene and -protein interactions [ 4–6 ], and the discovery of novel drugs [ 7 , 8 ]. More importantly, the unique features of metabolites, as compared to proteins and nucleic acids, lead to a novel approach to use metabolites to revert biological phenotypes like antibiotic resistance, which is termed as reprogramming metabolomics [ 3 , 9 , 10 ].…”