Oxygen restriction as challenge test reveals early high-fat-diet-induced changes in glucose and lipid metabolism

Abstract

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 an animal experiment. Oxygen restriction (OxR; based on ambient, mild normobaric hypoxia) is a non-invasive challenge test that measures the flexibility to adapt metabolism. Metabolic inflexibility is one of the hallmarks of the metabolic syndrome. To test whether OxR can be used to reveal early diet-induced health effects, we exposed mice to a low-fat (LF) or high-fat (HF) diet for only 5 days. The response to OxR was assessed by calorimetric measurements, followed by analysis of gene expression in liver and epididymal white adipose tissue (eWAT) and serum markers for e.g. protein glycation and oxidation. Although HF feeding increased body weight, HF and LF mice did not differ in indirect calorimetric values under normoxic conditions and in a fasting state. Exposure to OxR; however, increased oxygen consumption and lipid oxidation in HF mice versus LF mice. Furthermore, OxR induced gluconeogenesis and an antioxidant response in the liver of HF mice, whereas it induced de novo lipogenesis and an antioxidant response in eWAT of LF mice, indicating that HF and LF mice differed in their adaptation to OxR. OxR also increased serum markers of protein glycation and oxidation in HF mice, whereas these changes were absent in LF mice. Cumulatively, OxR is a promising new method to test food products on potential beneficial effects for human health.

A Difference in Fatty Acid Composition of Isocaloric High-Fat Diets Alters Metabolic Flexibility in Male C57BL/6JOlaHsd Mice

“…An increase in glucose oxidation is considered advantageous during OxR since the oxidation of glucose requires less oxygen than the oxidation of an equimolar amount of fat. Furthermore, an increase in glucose oxidation can prevent the increase in blood glucose levels that is often seen during OxR [ 9 ]. The analysis of blood glucose levels before and after exposure to OxR revealed a (statistical) interaction between the diet (HFpu and HFs) and oxygen level (OxR and normoxia) because HFpu and HFs responded differently to the exposure.…”

“…Indirect calorimetry during OxR was performed as described [ 9 , 10 ]. For the exposure to OxR we used the same fasting regime as during the response to fasting and re-feeding (mice received 1.5 gram of feed at the start of the dark phase).…”

“…Such a challenge can consist of administration of a single nutrient, such as glucose [ 4 , 5 ] or lipid [ 6 ], or a combination of nutrients like in a meal test [ 7 , 8 ]. Alternatively, it can consist of exposure to an environmental challenge, such as oxygen restriction (OxR), in which a major determinant for aerobic fuel oxidation—oxygen—is limited [ 9 , 10 ]. An adequate response to the challenge, ultimately, requires substrate switching, which is impaired when metabolic flexibility declines.…”

“…The first diet (HFpu diet) is a standardized HF diet that was used in several previous studies [ 9 , 26 – 28 ] and mainly contains PUFAs in the fat fraction. The second diet (HFs diet) is identical to the HFpu diet, except for the fat fraction that mainly contains saturated fatty acids from palm oil.…”

Nutrigenomics of Body Weight Regulation: A Rationale for Careful Dissection of Individual Contributors

“…This is complemented by analysis of changes in the plasma and serum proteome. Recently, for example, we have observed that changes in oxidative stress gene expression profile in WAT under different dietary conditions, is reflected by a serum marker for protein oxidation [ 112 ]. As an alternative to metabolome and proteome analysis of serum/plasma, transcriptome analysis of peripheral blood mononuclear cells (PBMC) is increasingly used [ 113 , 114 ].…”