Metabolic adaptation of white adipose tissue to acute, short-term environmental oxygen restriction in mice [Mus musculus]

Duivenvoorde, Loes; Schothorst, Evert van; Romijnders-van der Stelt, Inge; Hoek, Elise; Keijer, Jaap


White adipose tissue (WAT) expansion during e.g. obesity reduces oxygen availability in WAT in mice. Little is known on the adaptation of WAT to mild environmental oxygen restriction (OxR). Therefore, we studied metabolic adaptation to acute OxR in fasted, diet-induced moderately obese mice that were exposed to mild hypoxic (12% O2) or normoxic (20.9% O2) conditions for only 6 hours. Adaptation was assessed by determination of amino acids and (acyl)carnitines levels in serum and WAT, and by whole genome expression analysis in WAT. Adaptation was also assessed during the exposure using indirect calorimetry. We found that OxR reduced mitochondrial oxidation at whole-body level, as shown by a reduction in whole-body oxygen consumption and an increase in serum long-chain acylcarnitine levels. WAT did not seem to contribute to this serum profile since only short-chain acylcarnitines were increased in WAT and gene expression analysis indicated an increase in mitochondrial oxidation, based on coordinate down-regulation of Sirt4, Gpam and Chchd3/Minos3. In addition, OxR did not induce oxidative stress in obese WAT, but increased molecular pathways involved in cell growth and proliferation. OxR increased levels of tyrosine, lysine and ornithine in serum and of leucine/isoleucine in WAT. This study shows that OxR limits oxidative phosphorylation at whole-body level, but in WAT compensatory mechanisms seem to operate. The down-regulation of the mitochondria-related genes Sirt4, Gpam, and Chchd3 may be considered as a biomarker profile for WAT mitochondrial reprogramming in response to acute exposure to limited oxygen availability