Oxygen restriction as challenge test reveals early diet-induced health effects

Background and aims: Challenge tests stress homeostasis and may reveal deviations in health that remain masked under unchallenged conditions. Ideally, challenge tests are non-invasive and applicable in an early phase of a study. The response to oxygen restriction (OxR; mild normobaric 12% O2) measures the flexibility to adapt metabolism. Metabolic inflexibility is one of the hallmarks of the metabolic syndrome and underlying insulin resistance. Materials and methods: Male C57BL/6JOlaHsd adult mice were fed a low-fat (LF) or high-fat (HF) diet for only five days. Indirect calorimetry was used to assess the response to OxR. Serum markers, including protein glycation/oxidation, and gene expression in liver and white adipose tissue (WAT) were analyzed. Results: Although HF-fed mice had a significant higher body weight (BW) after five days of feeding, HF-fed and LF-fed mice did not differ in calorimetric values under normal conditions nor in fasting state. Moreover, the subgroups of mice that were fasted and exposed to OxR during the last 6h showed no differences in BW (gain), nor in blood glucose levels. Exposure to OxR, however, revealed significant differences in substrate use with the HF-fed mice showing higher fatty acid oxidation levels and oxygen consumption, while their activity was similar to LF-fed mice. Furthermore, hepatic and WAT transcript levels differed significantly between both groups indicating differences in their adaptation to OxR. Only HF-fed mice showed increased hepatic lactate/glucose metabolism upon OxR, while LF-fed mice showed an increased oxidative stress response in WAT. The adaptation in HF mice appeared to be dampened, associated with increased serum markers of protein glycation/oxidation, whereas these changes were absent in LF mice. Conclusion: An oxygen restriction challenge test is a promising new method to test food products on potential beneficial effects for metabolic health.