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

  • Integrative physiology
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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.

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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.

Ethical standards

The experimental protocol was approved by the Animal Welfare Committee of Wageningen University, Wageningen, The Netherlands (DEC2012035).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Human and Animal Physiology, Wageningen University, De Elst 1, 6708 WD, Wageningen, The Netherlands

    Loes P. M. Duivenvoorde, Evert M. van Schothorst, Davina Derous, Inge van der Stelt & Jaap Keijer

  2. Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, UK

    Jinit Masania, Naila Rabbani & Paul J. Thornalley

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  1. Loes P. M. Duivenvoorde
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Correspondence to Jaap Keijer.

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Suppl. fig. 1

Schematic overview of the study design and exposure to OxR. The complete study lasted for three weeks. 48 male mice arrived at 10 weeks of age. After three weeks on the low-fat diet, mice were stratified and individually housed in the indirect calorimetry system. Mice could adapt to the InCa system for 24 h after which 24 mice received a fresh batch of LF diet and 24 mice switched to the high-fat diet. After 5 days of HF- or LF feeding, mice were exposed to OxR or remained under normal air conditions for 6 hours. Mice were fasted by providing them a restricted amount of feed at the start of the dark phase (18.00 h) preceding the OxR or normoxic challenge. The restricted amount of feed is generally consumed within 6 hours (around 0.00 h). Around 5.00 h, all mice were in a fasted state (RER < 0.8). For the LFo and HFo mice, oxygen is decreased from 20.9 % to 12 % from 7.00 h to 7.30 h. LFn and HFn mice remained under normoxic conditions. Indirect calorimetry values during OxR or normoxia were then recorded from 7.30 h to 13.30 h, after which mice were immediately sacrificed. (PDF 44 kb)

Suppl. fig. 2

Relative gene expression in liver tissue and WAT of LF and HF mice that were either exposed to OxR or normoxic air. Gene expression in liver (a) and WAT (b) was calculated relatively to the geometric mean of the reference genes. Sod1, superoxide dismutase 1; Sod2, superoxide dismutase 2; Ucp2, uncoupling protein 2; Slc2a2, solute carrier family 2 (facilitated glucose transporter; Glut2); Pdk1, pyruvate dehydrogenase kinase 1; Pklr, pyruvate kinase; Pck1phosphoenolpyruvatecarboxykinase 1 (Pepck); Ldha, lactate dehydrogenase A; Slc16a1, solute carrier family 16 (Mct1); Pcx, pyruvate carboxylase; Me1, malic enzyme; Txnrd2, thioredoxinreductase 2; Vegfa, vascular endothelial growth factor A; Ppargrc1a peroxisome proliferative activated receptor gamma coactivator 1 alpha (Pgc1a); Cs, citrate synthase; Cpt1a, carnitinepalmitoyltransferase 1a; Pnpla2, patatin-like phospholipase domain containing 2; Acaca, acetyl-Coenzyme A carboxylase alpha; Acly, ATP citrate lyase; Elovl6, ELOVL family member 6, elongation of long chain fatty acids; Fasn, fatty acid synthase; Scd1, stearoyl-Coenzyme A desaturase 1 (PDF 50 kb)

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Duivenvoorde, L.P.M., van Schothorst, E.M., Derous, D. et al. Oxygen restriction as challenge test reveals early high-fat-diet-induced changes in glucose and lipid metabolism. Pflugers Arch - Eur J Physiol 467, 1179–1193 (2015). https://doi.org/10.1007/s00424-014-1553-8

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