Abstract
Adipose tissue takes up glucose and releases lactate, thereby contributing significantly to systemic glucose and lactate homeostasis. This implies the necessity of upregulation of net acid and lactate flux capacity during adipocyte differentiation and function. However, the regulation of lactate- and acid/base transporters in adipocytes is poorly understood. Here, we tested the hypothesis that adipocyte thermogenesis, browning and differentiation are associated with an upregulation of plasma membrane lactate and acid/base transport capacity that in turn is important for adipocyte metabolism. The mRNA and protein levels of the lactate-H+ transporter MCT1 and the Na+,HCO3− cotransporter NBCe1 were upregulated in mouse interscapular brown and inguinal white adipose tissue upon cold induction of thermogenesis and browning. MCT1, MCT4, and NBCe1 were furthermore strongly upregulated at the mRNA and protein level upon differentiation of cultured pre-adipocytes. Adipocyte differentiation was accompanied by increased plasma membrane lactate flux capacity, which was reduced by MCT inhibition and by MCT1 knockdown. Finally, in differentiated brown adipocytes, glycolysis (assessed as ECAR), and after noradrenergic stimulation also oxidative metabolism (OCR), was decreased by MCT inhibition. We suggest that upregulation of MCT1- and MCT4-mediated lactate flux capacity and NBCe1-mediated HCO3−/pH homeostasis are important for the physiological function of mature adipocytes.
Highlights
Been linked to metabolic disturbances such as obesity and diabetes[6,10,11,12]
Immunoblotting analysis of cell lysates harvested before and after differentiation showed that the protein expression levels of MCT1 (Fig. 2d), MCT4 (Fig. 2e) and NBCe1 were likewise increased upon differentiation, qualitatively consistent with the mRNA data, specific levels in the different cell lines varied. These results show that MCT1, MCT4, and NBCe1 mRNA and protein levels are robustly increased upon adipocyte differentiation
The inhibitor had no detectable effect on the differentiation per se, nor on the expression levels of MCT1 and −4, in any of the three cell types. These results show that lactate transport capacity is increased upon adipocyte differentiation and that MCT1 appears to be responsible for a substantial fraction of the lactate influx capacity of differentiated adipocytes
Summary
Been linked to metabolic disturbances such as obesity and diabetes[6,10,11,12]. Basal lactate production from WAT is increased in obese humans, due to the increased WAT mass[12]. Since cellular pH is continually challenged by the CO2 and H+ produced during mitochondrial respiration and ATP hydrolysis, respectively[25], we asked whether bicarbonate transporters are upregulated during adipocyte differentiation. MCT1 and MCT4 and NBCe1 are upregulated at the mRNA and protein level during white and brown adipocyte differentiation in vitro. Differentiation-induced MCT1 and MCT4 upregulation is accompanied by a marked increase in lactate flux capacity, predominately mediated by MCT1, and MCT inhibition strongly attenuates β-adrenergically induced metabolic activity. These data point to important roles for acid-base transport in adipocyte function
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