We have previously shown rats selectively bred for low aerobic fitness (low capacity runner, LCR) are highly susceptible to high-fat/high-sucrose (HFHS) diet-induced weight gain and metabolic dysfunction. Conversely, rats bred for high aerobic fitness (high capacity runner, HCR) are protected against HFHS diet-induced pathologies. In addition, HCRs consistently display higher energy expenditure (EE) and metabolic flexibility than LCRs. A microarray of the liver suggests the adaptability of HCRs to the HFHS diet is associated with an upregulation in bile acid (BA) synthesis. This is supported by HCRs having greater fecal BA excretion, hepatic expression of BA synthesis genes, and serum 7α-hydroxy-4-cholesten-3-one (C4), a proxy measure of BA synthesis. Cholestyramine (CSM) is a BA sequestrant that functions by binding BAs in the gastrointestinal tract and disrupting enterohepatic circulation. Herein we examined if CSM treatment could reduce HFHS-induced weight gain and adiposity in LCRs by increasing EE via promotion of fecal BA excretion and subsequent production.


HCR and LCR rats were fed a 1-week HFHS diet (45% fat, 17% sucrose, 4.73 kcal/g) with or without CSM (HFC, 2%/wt, 4.63/kcal).


After 1-week, LCRs gained 60% more weight on HFHS compared to HCRs. HFC feeding resulted in ~60% less weight gain in both strains compared to HFHS. Importantly, ~100% of LCR weight gain was fat mass regardless of diet, while the HCR gained ~50%/50% fat and fat-free mass. LCRs had a higher average respiratory quotient (RQ) than HCRs regardless of diet, suggesting reduced lipid utilization. Both strains had significant reductions in RQ during the 1-week HFC feeding. LCRs had greater 1-week energy intake (EI) than HCR regardless of diet, and HFC feeding reduced EI in both strains.


Together, these data suggest CSM treatment may mitigate susceptibility to diet-induced weight gain associated with low aerobic fitness, partly through increased lipid for energy utilization, and reduced EI.