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Rats selectively bred for the high intrinsic aerobic capacity runner (HCR) or low aerobic capacity runner (LCR) show pronounced differences in susceptibility for high-fat/high sucrose (HFHS) diet-induced hepatic steatosis and insulin resistance, replicating the protective effect of high aerobic capacity in humans. We have previously shown multiple systemic differences in energy and substrate metabolism that impacts steatosis between HCR and LCR rats. This study aimed to investigate hepatic-specific mechanisms of action via changes in gene transcription. Livers of HCR rats had a greater number of genes that significantly changed in response to 3-day HFHS compared with LCR rats (171 vs. 75 genes: >1.5-fold, p < 0.05). HCR and LCR rats displayed numerous baseline differences in gene expression while on a low-fat control diet (CON). A 3-day HFHS diet resulted in greater expression of genes involved in the conversion of excess acetyl-CoA to cholesterol and bile acid (BA) synthesis compared with the CON diet in HCR, but not LCR rats. These results were associated with higher fecal BA loss and lower serum BA concentrations in HCR rats. Exercise studies in rats and mice also revealed higher hepatic expression of cholesterol and BA synthesis genes. Overall, these results suggest that high aerobic capacity and exercise are associated with upregulated BA synthesis paired with greater fecal excretion of cholesterol and BA, an effect that may play a role in protection against hepatic steatosis in rodents., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Low aerobic capacity increases the risk for insulin resistance but the mechanisms are unknown. In this study, we tested susceptibility to acute (3-day) high-fat, high-sucrose diet (HFD)-induced insulin resistance in male rats selectively bred for divergent intrinsic aerobic capacity, that is, high-capacity running (HCR) and low-capacity running (LCR) rats. We employed hyperinsulinemic-euglycemic clamps, tracers, and transcriptome sequencing of skeletal muscle to test whether divergence in aerobic capacity impacted insulin resistance through systemic and tissue-specific metabolic adaptations. An HFD evoked decreased insulin sensitivity and insulin signaling in muscle and liver in LCR rats, whereas HCR rats were protected. An HFD led to increased glucose transport in skeletal muscle (twofold) of HCR rats while increasing glucose transport into adipose depots of the LCR rats (twofold). Skeletal muscle transcriptome revealed robust differences in the gene profile of HCR vs LCR on low-fat diet and HFD conditions, including robust differences in specific genes involved in lipid metabolism, adipogenesis, and differentiation. HCR transcriptional adaptations to an acute HFD were more robust than for LCR and included genes driving mitochondrial energy metabolism. In conclusion, intrinsic aerobic capacity robustly impacts systemic and skeletal muscle adaptations to HFD-induced alterations in insulin resistance, an effect that is likely driven by baseline differences in oxidative capacity, gene expression profile, and transcriptional adaptations to an HFD., (Copyright © 2019 Endocrine Society.)

Objective: Aerobic capacity is the most powerful predictor of all-cause mortality in humans; however, its role in the development of obesity and susceptibility for high-fat diet (HFD)-induced weight gain is not completely understood., Methods: Herein, a rodent model system of divergent intrinsic aerobic capacity [high capacity running (HCR) and low capacity running (LCR)] was utilized to evaluate the role of aerobic fitness on 1-week HFD-induced (45% and 60% kcal) weight gain. Food/energy intake, body composition analysis, and brown adipose tissue gene expression were assessed as important potential factors involved in modulating HFD-induced weight gain., Results: HCR rats had reduced 1-week weight gain on both HFDs compared with LCR. Reduced HFD-induced weight gain was associated with greater adaptability to decrease food intake following initiation of the HFDs. Further, the HCR rats were observed to have reduced feeding efficiency and greater brown adipose mass and expression of genes involved in thermogenesis., Conclusions: Rats with high intrinsic aerobic capacity have reduced susceptibility to 1-week HFD-induced weight gain, which is associated with greater food intake adaptability to control intake of energy-dense HFDs, reduced weight gain per kcal consumed, and greater brown adipose tissue mass and thermogenic gene expression., (© 2016 The Obesity Society.)

Aerobic capacity/fitness significantly impacts susceptibility for fatty liver and diabetes, but the mechanisms remain unknown. Herein, we utilized rats selectively bred for high (HCR) and low (LCR) intrinsic aerobic capacity to examine the mechanisms by which aerobic capacity impacts metabolic vulnerability for fatty liver following a 3-day high-fat diet (HFD). Indirect calorimetry assessment of energy metabolism combined with radiolabeled dietary food was employed to examine systemic metabolism in combination with ex vivo measurements of hepatic lipid oxidation. The LCR, but not HCR, displayed increased hepatic lipid accumulation in response to the HFD despite both groups increasing energy intake. However, LCR rats had a greater increase in energy intake and demonstrated greater daily weight gain and percent body fat due to HFD compared with HCR. Additionally, total energy expenditure was higher in the larger LCR. However, controlling for the difference in body weight, the LCR has lower resting energy expenditure compared with HCR. Importantly, respiratory quotient was significantly higher during the HFD in the LCR compared with HCR, suggesting reduced whole body lipid utilization in the LCR. This was confirmed by the observed lower whole body dietary fatty acid oxidation in LCR compared with HCR. Furthermore, LCR liver homogenate and isolated mitochondria showed lower complete fatty acid oxidation compared with HCR. We conclude that rats bred for low intrinsic aerobic capacity show greater susceptibility for dietary-induced hepatic steatosis, which is associated with a lower energy expenditure and reduced whole body and hepatic mitochondrial lipid oxidation.

Changes in substrate utilization and reduced mitochondrial respiratory capacity following exposure to energy-dense, high-fat diets (HFD) are putatively key components in the development of obesity-related metabolic disease. We examined the effect of a 3-day HFD on isolated liver mitochondrial respiration and whole body energy utilization in obesity-prone (OP) rats. We also examined if hepatic overexpression of peroxisomal proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial respiratory capacity and biogenesis, would modify liver and whole body responses to the HFD. Acute, 3-day HFD (45% kcal) in OP rats resulted in increased daily energy intake, energy balance, weight gain, and adiposity, without an increase in liver triglyceride (triacylglycerol) accumulation. HFD-fed OP rats also displayed decreased whole body substrate switching from the dark to the light cycle, which was paired with reductions in hepatic mitochondrial respiration of multiple substrates in multiple respiratory states. Hepatic PGC-1α overexpression was observed to protect whole body substrate switching, as well as maintain mitochondrial respiration, following the acute HFD. Additionally, liver PGC-1α overexpression did not alter whole body dietary fatty acid oxidation but resulted in greater storage of dietary free fatty acids in liver lipid, primarily as triacylglycerol. Together, these data demonstrate that a short-term HFD can result in a decrease in metabolic flexibility and hepatic mitochondrial respiratory capacity in OP rats that is completely prevented by hepatic overexpression of PGC-1α.