Intrinsic high aerobic capacity in male rats protects against diet-induced insulin resistance

Authors: MORRIS E., MATTHEW - University Of Kansas Medical School; MEERS, GRACE M.E. - University Of Missouri; RUEGSEGGER, GREGORY - University Of Missouri; WANKHADE, UMESH - Arkansas Children'S Nutrition Research Center (ACNC); ROBINSON, TOMMY - University Of Kansas Medical School; KOCH, LAUREN - University Of Toledo; BRITTON, STEVEN - University Of Michigan; R., SCOTT - University Of Missouri; SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC); THYFAULT, JOHN - University Of Kansas

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/2/2019
Publication Date: 5/1/2019
Citation: Morris E., M., Meers, G., Ruegsegger, G.N., Wankhade, U.D., Robinson, T., Koch, L.G., Britton, S.L., R., S., Shankar, K., Thyfault, J.P. 2019. Intrinsic high aerobic capacity in male rats protects against diet-induced insulin resistance. Endocrinology. 160(5):1179-1192. https://doi.org/10.1210/en.2019-00118.
DOI: https://doi.org/10.1210/en.2019-00118

Interpretive Summary: Individuals with low aerobic capacity (a surrogate for overall fitness) is at high risk of developing resistance to the blood sugar-regulating hormone insulin; this insulin resistance is a precursor to type 2 diabetes. Using a rat model in which animals have high or low fitness levels, investigators tested the status of insulin signaling and movement of glucose into tissues by using the 'gold-standard' insulin clamp technique. These studies done in animals with a short exposure to high fat diets (for 3 days) showed that animals with high intrinsic fitness were able to increase disposal of glucose into the skeletal muscle at levels twice as rats with low fitness. On the other hand, animals with low fitness transferred more glucose to fat tissue (adipose tissue) under these conditions of overnutrition. Since excess adipose tissue and poor glucose utilization in muscle are harbingers of diabetes, these studies suggest that intrinsic fitness robustly impacts hormonal systems regulating insulin sensitivity and risk of diabetes, and that higher levels of overall physical fitness are protective.

Technical Abstract: 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.