Abstract

The in vitro oxygen microenvironment profoundly affects the capacity of cell cultures to model physiological and pathophysiological states. Cell culture is often considered to be hyperoxic, but pericellular oxygen levels, which are affected by oxygen diffusivity and consumption, are rarely reported. Here, we provide evidence that several cell types in culture actually experience local hypoxia, with important implications for cell metabolism and function. We focused initially on adipocytes, as adipose tissue hypoxia is frequently observed in obesity and precedes diminished adipocyte function. Under standard conditions, cultured adipocytes are highly glycolytic and exhibit a transcriptional profile indicative of physiological hypoxia. Increasing pericellular oxygen diverted glucose flux toward mitochondria, lowered HIF1a activity, and resulted in widespread transcriptional rewiring. Functionally, adipocytes increased adipokine secretion and sensitivity to insulin and lipolytic stimuli, r...

Authors	Tan, J; Virtue, S; Norris, DM; Conway, OJ; Yang, M; Bidault, G; Gribben, C; Lugtu, F; Kamzolas, I; Krycer, JR; Mills, RJ; Liang, L; Pereira, C; Dale, M; Shun-Shion, AS; Baird, HJ; Horscroft, JA; Sowton, AP; Ma, M; Carobbio, S; Petsalaki, E; Murray, AJ; Gershlick, DC; Nathan, JA; Hudson, JE; Vallier, L; Fisher-Wellman, KH; Frezza, C; Vidal-Puig, A; Fazakerley, DJ
Journal	The EMBO journal
Pages	2127-2165
Volume	43
Date	5/05/2024
Grant ID	FS/17/61/33473 | British Heart Foundation (BHF); New-Chol | EC | ERC | HORIZON EUROPE European Research Council (ERC); Senior Clinical Research Fellowship | Wellcome Trust (WT); BB/W005905/1 | UKRI | Biotechnology and Biological Sciences Research Council (BBSRC); PhD Studentship | UKRI | Medical Research Council (MRC); BB/F016581/1 | UKRI | Biotechnology and Biological Sciences Research Council (BBSRC); MRC_MC_UU_12022/6 | UKRI | Medical Research Council (MRC); 204845/Z/16/Z | Wellcome Trust (WT); Wellcome Trust [WT_] (United Kingdom); PhD Studentship | Wellcome Trust (WT); MR/S007091/1 | UKRI | Medical Research Council (MRC); Sir Henry Dale Fellowship | Wellcome Trust (WT); DOD-W81XWH-19-1-0213 | DOD | Department of Defense Education Activity (DoDEA); MC_UU_00014/5 | Medical Research Council [MRC_] (United Kingdom); Snow Medical Fellowship | Snow Medical (SnowMedical); RG/18/7/33636 | British Heart Foundation (BHF); MC_UU_12012/2 | UKRI | Medical Research Council (MRC)
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s44318-024-00084-7