Hypoxia has been proposed to occur in hypertrophied adipose tissue(Reference Trayhurn and Wood1, Reference Trayhurn, Wang and Wood2) and may underlie the inflammatory response in the tissue and the subsequent development of obesity-associated disorders. Adipocytes switch to a glycolytic metabolism in response to hypoxia, involving an up-regulation of glucose transporter expression (particularly GLUT-1) and increased glucose uptake(Reference Wood, Wang and Lorente-Cebrián3). Consequently, lactate rises and needs to be removed from the cell. The transport of lactate, and similar metabolites, is mediated through the proton-linked MCT family. Currently, there are fourteen known MCT, four of which (MCT-1–4) transport lactate(Reference Meredith and Christian4). One transporter, MCT-4, has been reported to be up regulated by hypoxia in certain cell types(Reference Ullah, Davies and Halestrap5). The objective of the present study was to determine whether the MCT-1–4 are expressed in human adipocytes and whether hypoxia modulates their expression.
Human SGBS adipocytes were used to screen for the expression of the MCT-1–4 genes by RT–PCR. Adipocytes at day 14 post induction of differentiation were cultured under normoxia (21% (v/v) O2) or hypoxia (1% (v/v) O2) for different periods and MCT mRNA levels quantified by quantitative PCR. Another group of cells was treated with the hypoxia mimetic, CoCl2, to assess whether the key hypoxia-responsive transcription factor hypoxia-inducible factor 1 (HIF-1)(Reference Semenza6) was involved in any changes.
The ubiquitous MCT-1 was found to be expressed in both preadipocytes (0 d) and fully-differentiated adipocytes, as was MCT-2 and MCT-4 (Figure). Expression of MCT-3 was less clear. Hypoxia significantly increased lactate levels in the culture medium, and had a significant effect on MCT gene expression, up regulating MCT-1 and MCT-4 mRNA levels (8.5-fold and 14-fold respectively at 48 h; P<0.001), while down regulating MCT-2 (4-fold at 48 h; P<0.05). These changes on MCT gene expression were reversed on return to normoxia, and mirrored by CoCl2 treatment.
Figure. MCT1-4 mRNA in human adipocytes (SGBS cells) by RT-PCR.
The present study demonstrates for the first time that MCT-1, MCT-2 and MCT-4 are each expressed in human adipocytes. Furthermore, this expression is significantly modified by hypoxia in a type-specific manner, via the transcription factor HIF-1. MCT-1 and MCT-4 are likely to be important in exporting increased lactate produced by adipocytes under the hypoxic conditions that appear to characterize adipose tissue in obesity; besides, lactate may impact on the development of local inflammatory processes(Reference Samuvel, Sundararaj and Nareika7). Therefore, the observed hypoxia-related increase in lactate transport from adipocytes could constitute a further link between obesity, inflammation and the metabolic syndrome.
