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

Loes P M Duivenvoorde, Evert M van Schothorst, Davina Derous, Inge van der Stelt, Jinit Masania, Naila Rabbani, Paul J Thornalley, Jaap Keijer

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8 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1179-1193
Number of pages15
JournalPflugers Archiv : European Journal of Physiology
Issue number6
Early online date1 Jul 2014
Publication statusPublished - Jun 2015

Bibliographical note

Acknowledgments This work was supported by the European Union’s Seventh Framework Program FP7 2007–2013 under grant agreement no. 244995 (BIOCLAIMS Project). Furthermore, we would like to thank all members of Human and Animal Physiology for their helpful contributions, especially Hans Swarts, Dylan Eikelenboom and Esther Steenbergh for their help during the animal experiment and the analysis of gene expression.


  • hypoxia
  • metabolism
  • high-fat diet
  • obesity
  • oxidative stress
  • indirect calorimetry


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